Anticholinergic neuroprotective composition and methods

ABSTRACT

The present invention relates to a pharmaceutical composition comprising propiverine, trospium or glycopyrrolate; and a non-anticholinergic antiemetic agent. It is also related to a pharmaceutical composition comprising a high dose of solifenacin or a pharmaceutically acceptable salts thereof; and a non-anticholinergic antiemetic agent. Pharmaceutical compositions containing high dose of nsPAChA for use for increasing the AChEI blood concentrations and for combating neurodegeneration are also described. The invention also relates to a method for inducing neuroprotection and combating neurodegeneration in a patient suffering from Alzheimer type dementia as well as to a method for increasing the blood levels of an acetyl choline esterase inhibitor (AChEI) in a human subject treated with an AChEI dose.

FIELD OF THE INVENTION

The invention relates to a pharmaceutical composition comprising (a) ahigh dose of a non-selective peripheral anticholinergic agent (nsPAChA)selected from the group consisting of propiverine and pharmaceuticallyacceptable salts thereof, trospium and pharmaceutically acceptable saltsthereof, glycopyrrolium and pharmaceutically acceptable salts thereof,and solifenacine and pharmaceutically acceptable salts thereof; (b) anon-anticholinergic antiemetic agent (naAEA); in admixture with apharmaceutical carrier; and (c) a high dose of an aceyticholine esteraseinhibitor (AChEI). This composition is useful for safely increasing theblood levels of an acetylcholinesterase inhibitor (AChEI) in a humantreated with said AChEI, thus reaching neuroprotective concentrations ofthe AChEI.

The invention provides the above pharmaceutical composition for use forsafely increasing AChEI plasma concentrations in a human subjectsuffering from Alzheimer type dementia in the treatment of said subjectwith said AChEI, thus inducing neuroprotection. The invention alsoprovides a pharmaceutical composition containing an nsPAChA dose frommore than 2- to 8-times the dose used in the anticholinergic therapy, inadmixture with a pharmaceutical carrier. Said composition is useful forinducing neuroprotection and combating neurodegeneration in a patienttreated with an AChEI dose of from 2.5 to 7 times the maximalrecommended dose of said AChEI.

The invention is related to a pharmaceutical composition containing ansPAChA dose from 100% to 800% the dose of said nsPAChA used in theanticholinergic therapy, in admixture with a pharmaceutical carrier, foruse for increasing the AChEI blood levels in humans. The invention alsoprovides a pharmaceutical composition comprising (a) a high dose of anon-selective peripheral anticholinergic agent (nsPAChA) selected fromthe group consisting of solifenacin and pharmaceutically acceptablesalts thereof; (b) a non anticholinergic antiemetic agent (naAEA); inadmixture with a pharmaceutical carrier. This composition is useful forsafely increasing the blood levels of an acetylcholinesterase inhibitor(AChEI) in a human treated with said AChEI, thus assuringneuroprotection.

The invention is also related to the above pharmaceutical compositionfor use for safely increasing AChEI blood levels in a human subjectsuffering from Alzheimer type dementia in the treatment of said subjectwith said AChEI, thus reaching neuroprotective concentrations of theAChEI.

The invention is related to a method for safely increasing AChEI bloodlevels in a human subject by administering to said subject the abovecomposition in combination with an overdose of said AChEI, said humansubject possibly being a patient suffering from Alzheimer type dementia.

The invention also provides a method for inducing neuroprotection in apatient suffering from Alzheimer type dementia, thus combatingneurodegeneration and slowing disease progression, by administering tosaid patient a dose of a non-selective, peripheral anticholinergic agent(nsPAChA) which is more than twice the dose of said nsPAChA used in theanticholinergic therapy, in combination with an overdose of anacetylcholinesterase inhibitor (AChEI), said overdose being from 2.5 to7 times the maximal recommended dose of said AChEI.

The invention also relates to a method for increasing the blood levelsof an acetylcholinesterase inhibitor (AChEI) in a human subject byadministering to said subject an overdose of said AChEI which is from2.5 times to 7 times its maximum recommended dose, in combination with adose of a non-selective, peripheral anticholinergic agent (nsPAChA)which is from 100% to 800% the dose of said nsPAChA used in theanticholinergic therapy, said human subject possibly being a patientsuffering from Alzheimer type dementia.

The invention also provides a method for safely increasing AChEI bloodlevels in a human subject by administering to said subject the abovecomposition in combination with an overdose of said AChEI, said humansubject possibly being a patient suffering from Alzheimer type dementia.

DEFINITIONS

“AChE”: Acetyl Choline Esterase.

-   “AChEI(s)”: Acetyl Choline Esterase Inhibitor(s).-   “nsPAChA(s)”: non-selective, peripheral AntiCholinergic Agent(s).-   “naAEA(s)”: non-anticholinergic AntiEmetic Agent(s).

“Non-selective” (or non selective): referred to nsPAChAs, applies toanticholinergic agents exhibiting inhibitory activity broadly across thevarious subtypes of muscarinic M-receptors, namely the M1-M5 receptors,as currently identified.

“Peripheral”: referred to nsPAChAs, applies to anticholinergics that arelargely unable (have a limited ability) to enter the central nervoussystem following systemic administration and thus do not affect brainfunction to a clinically appreciable degree. These drugs can includeboth quaternary and tertiary ammonium anticholinergic agents, especiallythose having low lipid solubility.

“MTD”: maximum (or maximal) tolerated dose, i.e. the highest dose of adrug or treatment that does not cause unacceptable side effects. Themaximum tolerated dose is determined in clinical trials by testingincreasing doses on different groups of people until the highest dosewith acceptable side effects is found (NCI Drug Dictionary).

“AChEI overdose”: an AChEI dose administered to a human subject, whichis at least 2.5 times the MTD or maximum recommended dose in said humansubject.

“Anticholinergic therapy”: the treatment with an anticholinergic agentof gastro-intestinal cramping, nausea, retching, vomiting, fecalincontinence, bladder spasms, urinary incontinence, overactive bladder,asthma, motion sickness, muscular spasms, and smooth muscle contractivedisorders or the treatment with an anticholinergic agent of side effectscaused by AChEIs including, but not limited to gastro-intestinalcramping, nausea, retching, vomiting, fecal incontinence, bladderspasms, urinary incontinence, overactive bladder, asthma, motionsickness, muscular spasms, and smooth muscle contractive disorders.

-   “CNS”: Central Nervous System.-   “CSF”: Cerebrospinal Fluid.-   “PNS”: Peripheral Nervous System.-   “IR”: Immediate Release of the active ingredient from a composition.-   “ER”: Extended Release (or sustained release) of the active    ingredient from a composition by any administration route.

BACKGROUND OF THE INVENTION

Reduced levels of neurotransmitters including acetylcholine have beenreported in dementias of the Alzheimer type. In particular, a deficit inacetylcholine-mediated transmission is thought to contribute to thecognitive and the neurobehavioral abnormalities associated with thesedisorders. Accordingly, drugs known to augment cholinergic transmissionin the CNS are the mainstay of current therapy.

AChEIs are now not only part of the standard of care for patientssuffering from a dementia of the Alzheimer type, but are also widelyused off-label for various other chronic progressive disorders ofcognitive function. AChEIs have the enhancement ofacetylcholine-mediated neurotransmission as a general mechanism ofaction. All act in the human CNS to increase and prolong theavailability of acetylcholine by inhibiting its degradatory enzymeacetylcholinesterase (AChE). Four AChEIs have been approved by the U.S.FDA for the treatment of Alzheimer's disease and for Parkinson's diseasedementia: tacrine, donepezil [Aricept®], rivastigmine [Exelon®] andgalantamine [Razadyne®]. AChEIs are available in various formulationsincluding immediate release forms such as tablets, capsules andsolutions as well as rapid dissolving and extended release forms fororal administration as well as those for parenteral (e.g. transdermal)administration.

In particular, tacrine is presented in capsules containing 10, 20, 30,40 mg/capsule and is used at recommended daily dosages of from 40 to 160mg (divided into 4 doses); donepezil is presented, as hydrochloride, inorally disintegrating tablets or in tablets to be swallowed containing 5or 10 mg/tablet to be administered once a day and is used at recommendeddaily dosages of from 5 to 10 mg, and as a dose formulation containing23 mg of donepezil HCl in a matrix type tablet to be administered once aday; rivastigmine is presented in capsules containing the hydrogentartrate in amounts corresponding to 1.5, 3, 4.5 and 6 mg ofrivastigmine base, as oral solution containing the tartratecorresponding to 2 mg of rivastigmine base and in form of a transdermalpatch releasing rivastigmine at 4.6 mg/24 hours or 9.5 mg/24 hours, therecommended daily dosage for the IR forms being of from 6 to 12 mg,divided into 2 doses and the maximal studied patch dose being 13.3 mg/24hours the maximal recommended patch dose being 18 mg/24 hours; andgalantamine is available in ER capsules of 8 mg, 16 mg and 24 mgcontaining 10.253 mg, 20.506 mg and 30.758 mg, respectively, ofgalantamine hydrobromide, or in IR tablets containing 5.126, 10.253, and15.379 mg of galantamine hydrobromide, respectively, corresponding to 4mg, 8 mg and 12 mg, respectively, of galantamine base and as a 4 mg/mLoral solution, the recommended daily dosage being from 16 mg to 32 mg,in the United States of America the maximum recommended daily dosehaving been reduced to 24 mg divided into 2 doses.

Brief reviews of the efficacy of the AChEIs rivastigmine, donepezil andgalantamine for the treatment of dementia diseases, by Angelescu et al.,have been published in MMW-Fortschr. Med. Sonderheit, 2007, 149, 76-78(“Angelescu 2007”) and in the Cochrane Database Syst Review, 2006, Jan.25(1): CD005593 (“Birks, 2006”).

Other AChEIs, in particular tacrine analogs, such as ipidacrine;phenserine and their analogs; icopezil; and zanapezil are underevaluation. For example, phenserine is administered in IR 15 mg tabletsand has been studied at a daily dose of 30 mg.

AChEIs vary in their pharmacological profiles and in their affinitiesfor acetylcholinesterase and butyrylcholinesterase. Donepezil andgalantamine are 1000- and 50-fold, respectively, more selective foracetylcholinesterase than for butyrylcholinesterase, whereasrivastigmine inhibits both enzymes with similar affinity (Thomsen etal., Life Scie. 1990, 46, 1553-58) and certain analogs of phenserine aremore selective for butyrylcholinesterase (see for example Qian-sheng Yuet al., J Med Chem, 1997, 40(18), 2895-2898 and U.S. Pat. No.6,683,105).

Carefully conducted clinical trials of donepezil (Rogers et al.,Neurology 1998, 50, 136-45; Winblad et al. Neurology. 2001 Aug. 14;57(3):489-95), rivastigimine (Rösler et al., Brit. Med. J. 1999, 318,633-38; Farlow et al. Eur. Neurol., 2000, 44, 236-41) and galantamine(Raskind et al., Neurology, 2000, 54, 2261-68; Tariot et al., Neurology,2000, 54, 2269-76) in patients with dementias of the Alzheimer typedemonstrated small, but statistically significant, benefits on cognitiveand global measures relevant to dementia. The magnitude of the effect inpivotal clinical trials was on the order of a 2.8 point improvement onthe 70-point cognitive subscale of the Alzheimer's Disease AssessmentScale (ADAS-Cog), or 1-1.5 point improvement on the 30-point Mini-MentalStatus Examination (MMSE) compared to placebo over six months.Differences in global measures assessed by the 7-point ClinicianInterview-Based Impression of Change scale (CIBIC) were on the order of0.3-0.5 points in patients receiving an AChEI compared to thosereceiving placebo. Efficacy was similar for the three commonly usedAChEIs. AChEIs also appear to have a beneficial effect on the behavioraland neuropsychiatric symptoms in patients with Alzheimer type dementias.Moreover, rivastigmine was given open-label to patients with Parkinson'sdisease (PD) at an initial dose of 1.5 mg twice a day and the dose wasincreased after 4 weeks to 3 mg twice daily, after 8 weeks to 4.5 mgtwice daily and after 12 weeks to a maximal dose of 6 mg twice daily bytrying to keep the dose of rivastigmine constant at the maximaltolerated dose, between weeks 12 and 26 of the trial. According to theAuthors, rivastigmine may improve the cognitive functions in PD patientswith dementia with no worsening of motor function. (Giladi et al., ActaNeurol Scand 2003, 108, 368-373).

Unfortunately, however, none of the currently available medicationsoffer more than modest clinical benefit for some patients suffering fromany of the aforementioned dementing disorders, even when thesemedications are administered at their maximum safe and tolerated doses.This is the first problem limiting the success of current AChEI therapyof Alzheimer type dementias.

A second problem limiting the success of current AChEI therapy ofAlzheimer type dementias is that, even at recommended amounts, all thesedrugs produce dose limiting adverse reactions, mainly byover-stimulating peripheral cholinergic receptors of the muscarinictype. As a result, signs and symptoms of untoward gastrointestinal,pulmonary, cardiovascular, urinary, and other systems dysfunction occur.These side effects commonly include, for the aforementioned AChEIstacrine, donepezil, rivastigmine and galantamine: anorexia, nausea,vomiting, diarrhea, abdominal pain, weight loss; increased bronchialsecretions, dyspnea, bronchoconstriction and bronchospasm; bradycardia,supraventricular cardiac conduction abnormalities, vasodilation,hypotension, dizziness and syncope; urinary bladder spasm, increasedurinary frequency, and incontinence; flushing and diaphoresis; fatigue,headache, lacrymation, miosis, and loss of binocular vision (Physicians'Desk Reference 2008, Thomson P D R, Montvale, N.J.).

Adverse events attending the use of AChEIs appear to primarily reflectthe excessive stimulation of peripheral cholinergic receptors,especially those of the muscarinic type (mAChRs). Five subtypes ofmuscarinic receptors, M1 through M5, have now been identified. Ongoingresearch has begun to map the distribution and physiologic role of thesereceptors as well as determine the binding affinity of drugs to them.For example, M1 receptors are found in sympathetic postganglionicneurons (autonomic ganglia), in gastric tissue and in the myentericplexus; they are involved in secretions from salivary glands and thegastrointestinal tract. M2 receptors are present in cardiac and smoothmuscle and have been implicated in the regulation of contractile forcesof the atrial cardiac muscle and the conduction velocity of theatrioventricular node and thus heart rate. M2 receptors are also presenton gastrointestinal smooth muscle as well as on detrusor smooth musclecells and other structures within the bladder wall. M3 receptors are thepredominant muscarinic receptor subtype mediating contraction of thestomach fundus, urinary bladder, and trachea. They are also expressed onglandular cells including gastric parietal cells and on vascular smoothmuscle as well as detrusor smooth muscle and other structures within thebladder wall. M3 receptors are involved in exocrine gland secretion,smooth muscle contractility, emesis, pupil dilatation, food intake andweight gain.

It is also known that the degree to which AChEIs can attenuate theactivity of this enzyme (acetylcholinesterase, AChE) in the CNS can beestimated by assays of AChE activity and related protein levels in theCSF and by use of cerebral imaging technology. It is reported thatrecommended maximal dose levels of these drugs typically achieve onlyabout 35% AChE inhibition (without a concomitant increase in AChEprotein levels) in the CNS of Alzheimer disease patients (Brannan S etal. ACNP 46^(th) Annual Meeting, Program No. 4. Boca Raton Fla., Dec.10, 2007—“Brannan 2007”; Farlow M et al AAN Poster 2008; Davidsson P etal Neurosci Lett 2001; 300:157-60; Amici S et al Mech Ageing Dev 2001;122:2057-62) and that inhibition of AChE activity and cognitiveimprovement are significantly correlated (Giacobini et al. J NeuralTransm. 2002 July; 109(7-8):1053-65; Darreh-Shori T et al, J NeuralTrans 2006; 113:1791-801) and that, ordinarily, a higher degree ofenzyme blockade must be attained for maximum functional effect (Jann etal., Clin Pharmacokinet. 2002; 41(10):719-39—“Jann 2002”).

On the other hand, doubling the dose of rivastigmine, which becameclinically practical when AChEI administration by immediate releasetablets was replaced by skin patches, which diminished side effects byblunting peak blood levels, significantly increased the amount ofcognitive improvement in patients with Alzheimer's disease withoutincreasing side effects. Similarly, a 23 mg dose of donepezil formulatedin a matrix type tablet that tends to smooth out the sharp rise in peakdrug concentrations following once daily administration and facilitatesthe tolerable administration of a 23 mg dose, produces a significantlygreater cognitive benefit in Alzheimer Disease (AD) patients than theearlier 10 mg immediate-release dose formulation (Farlow et al, 2010).

The precise causes of the vomiting and related gastrointestinal symptomsso frequently induced by AChEI therapy are not established. Presumably,they reflect cholinergic receptor hyperstimulation attending AChEIadministration. Vomiting is coordinated in a center located at the baseof the brain. The vomiting center communicates with the nearbychemoreceptor trigger zone, whose stimulation can lead to suchcomplaints of gastrointestinal distress as anorexia, nausea andvomiting.

By virtue of being dose limiting, adverse effects also constrain theefficacy of AChEI therapy. Studies in animal models of human cognitivedysfunction indicate a direct dose-response relation between the amountof acetyl choline esterase inhibition and the degree of cognitiveimprovement (Bennett B M et al., Neuropsychopharmacology. 2007 March;32(3):505-513). Similar conclusions have been drawn regarding AChEIeffects on cognitive and behavioral symptoms in human patients withAlzheimer's disease (Jann 2002; Winblad B, Cummings J, Andreasen N,Grossberg G, Onofrj M, Sadowsky C, Zechner S, Nagel J, Lane R. Int JGeriatr Psychiatry. 2007 May; 22(5):456-67).

As set forth above, use of an AChEI to treat dementias of the Alzheimertype combined with a nsPAChA, which alleviates the peripheralcholinergic side effects of the AChEI, or combined with a naAEA, whichalleviates nausea and vomiting caused by the AChEI, fails to realize thefull potential benefits of this approach to therapy. While potentiallylessening side effects and thereby enabling the use of higher and thusmore effective doses of the AChEI, merely employing the concomitant useof antiemetics, such as domperidone and others, or of anticholinergicssuch as propantheline, oxybutynin, tolterodine and others, falls shortof achieving the utmost therapeutic advantages of AChEIs in thetreatment Alzheimer type dementias. Further implementation of thisconcept will confer far greater advantage to individuals suffering fromthese disorders.

An improvement in the treatment of Alzheimer type dementia is attainedby a combined therapy associating an nsPAChA, at a dose of from 20% to200% the current daily doses, with an AChEI, at a dose up to 4 times themaximal tolerated dose of said AChEI when administered alone, asdisclosed in WO 2009/120277. By such a treatment, a higheracetylcholinesterase inhibition in the CNS is achieved and greaterrelief of the symptoms of Alzheimer type dementia is enabled, byconcomitantly decreasing concurrent adverse effects.

Similarly, WO 2011/034568 discloses an improvement in the treatment ofAlzheimer type dementia which is attained by a combined therapyassociating a non-anticholinergic-antiemetic agent, at a dose of from50% to 300% the current IR daily doses, with an AChEI, at a dose up to 3times the recommended doses of said AChEI when administered alone.

Notwithstanding the real progress achieved by treating Alzheimer diseasepatients with up to 200% of the nsPAChA currently used doses in IR or ERforms or with up to 300% of the naAEAs currently used doses in IR formstogether with AChEIs, there is a need for further increasing AChEinhibition in the CNS of said patients.

There is substantial evidence from preclinical studies that AChEIs mayaffect basic processes that have been implicated in Alzheimer Disease(AD) pathogenesis, suggesting that these drugs could have bothdisease-modifying and neuroprotective effects in humans. The evidenceseems to be strongest in relation to donepezil (reviewed in Jacobson andSabbagh, 2008). There is also evidence from studies in Alzheimerpatients that these treatments could slow disease progression. Forexample Roundtree et al, (2009) report on 20-year retrospective studyconducted at an Academic center in 641 Alzheimer patients. In a linearmodel, greater anti-dementia drug use was significantly associated withslower rate of decline as measure on the Mini Mental State Examination(MMSE; p<0.0001), the ADAS-Cog (p<0.01), the Physical Self-MaintenanceScale (PMS; p<0.05), the Instrumental Activities of Daily Living (IADL;p<0.0001) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB;p<0.001). The magnitude of the treatment effect, however, was small.Rate of change in mean scores indicated that treated patients would havedeclined less on the rating scales: 1 point/year on the MMSE, 0.4points/year on the PMS, 1.4 point/year on the IADL, and 0.6 point/yearon the CDR-SB. Although clinically and statistically significant, thesetreatment effects remain modest (Shanks et al, Cholinesteraseinhibition: is there evidence for disease-modifying effects? Curr MedRes Opin, 2009, 25: 2439-46).

Studies in animal models of AD show a dose-response for neuro-protectionand suggest that the doses currently used in patients may be too low fordisease modification (i.e, slowing of disease progression). For example,a study by Dong et al (Hongxin Dong, Carla M. Yuede, Carolyn A.Coughlan, Keely M. Murphy, and John G. Csernansky. Effects of Donepezilon Amyloid-β and Synapse Density in the Tg2576 Mouse Model ofAlzheimer's Disease Brain Res. 2009 Dec. 15; 1303: 169-178) examined apossible neuro-protective effect of donepezil in a transgenic mousemodel of AD, the Tg2576 mouse model of AD. This model overexpresses thehuman amyloid precursor protein (hAPP), and is one of the most wellcharacterized mouse models of AD. In this model, at approximately 9months of age, A-beta deposits appear in cortical and limbic brainregions and indications of cellular inflammation and behavioral deficitsemerge (reviewed in Dong et al, 2009). In a previous study, Dong et al,(Hongxin Dong, Cynthia A. Csernansky, Maureen V. Martin, Amy Bertchume,Dana Vallera, and John G. Csernansky. Acetylcholinesterase inhibitorsameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer'sdisease. Psychopharmacology (Berl). 2005 August; 181(1): 145-152) hadshown that donepezil (0.1, 0.3 and 1.0 mg/kg for 6 weeks) improvedlearning and memory functions in Tg2576 mice, but did not affect A-betadeposition. In the “neuroprotective study,” (Dong et al, 2009), higherdoses of donepezil (0, 1, 2, and 4 mg/kg/day) were administeredchronically in drinking water to Tg2576 mice beginning at 3 months andending at 9 months of age, when A-beta deposits and behavioral deficitsusually become apparent. Concentrations of A-beta, synaptic protein(synaptophysin) and synapse density in the hippocampus were measuredfollowing the long-term administration of donepezil. Results showed thatadministration of 4 mg/kg/day of donepezil, as compared to vehicle,significantly reduced brain tissue soluble A-beta1-40 and 1-42, A-betaplaque number and burden. Furthermore, donepezil 4 mg/kg alsosignificantly increased synaptic density in the molecular layer of thedentate gyms of Tg2576 mice. Lower doses of donepezil (1 and 2 mg/kg)were not effective on these parameters. Taken together the results ofthe study show that a dose of 4 mg/kg/day of donepezil isneuroprotective in a mouse model of AD, but lower doses were noteffective. Thus, in Alzheimer patients, the administration of doseshigher than the currently approved doses of donepezil should beneuroprotective and should slow disease progression. A similardose-related neuroprotective effect has also been observed withrivastigmine and other AChEIs (Shanks et al. Cholinesterase inhibition:is there evidence for disease-modifying effects? Curr Med Res Opin 2009,October; 25 (10): 2439-46).

Thus, by further increasing the safe and tolerable dose of an AChEI itwill be possible to take advantage of their enhanced pharmacologicalactivity not only in relation to palliative effects but also in relationto neuroprotective effects, thus retarding progression of the underlyingdementing disorder.

However, as set forth above, even by using the method disclosed in WO2009/120277 or WO 2011/034568, it is presently not possible to increasealso beyond 4-times the therapeutic dose of AChEI to be administered toa patient without inducing intolerable cholinergic or emetic, from anyorigin, adverse effects, as those described above.

In particular, the increase of the AChEI doses by the concurrentsuppression of the peripheral cholinergic adverse effects, includingemesis, does not completely suppress vomiting caused by AChEI overdosesand, in any case, an antiemetic agent must be added to the AChEI. Byconsequence, if the AChEI doses are increased, the treated subjectshould take either a triple nsPAChA/AChEI/naAEA combination or annsPAChA/AChEI fixed combination and an antiemetic. Under theseconditions, on one side, it could be difficult to adjust the AChEI dosesin function of both the co-administered nsPAChA and antiemetic agent,and, on the other side, the administration of a triple combinationproviding concurrent or sequential, but separate AChEI, nsPAChA andantiemetic administrations could give rise to dangerous and even fatalmistakes in said administrations, especially in the context of thepopulation suffering from a dementia of Alzheimer type.

The present invention is directed to overcoming these and otherdeficiencies in the art.

SUMMARY OF THE INVENTION

The present invention is based on the realistic hypothesis that (a) theresults of Dong 2009 and Meunier 2006 (Meunier et al. The anti-amnesticand neuroprotective effects of donepezil against amyloid beta 25-35peptide-induced toxicity in mice involve interaction with the sigma1receptor. Br. J. Pharmacol, 2006, December; 149: 998-1012) areapplicable to humans, (b) there is a dose-effect relationship and (c) byincreasing the dose of donepezil, or of another AChEI, a neuroprotectiveeffect is induced.

By applying the results of Dong et al. and others to humans, it has beenobserved that the maximum recommended daily doses of the used AChEIs donot achieve the neuroprotective threshold for AChEIs. Even the recentmatrix type 23 mg dose of donepezil does not allow the attainment ofsaid threshold neuroprotective levels.

It has now been found that the Dong et al. results are applicable tohumans and that it is possible to safely reach and go above theneuroprotective threshold in the CNS. In fact, it has now beendiscovered that the nsPAChAs, when administered to a human being who istreated with a given dose of an AChEI, induce blood levels of said AChEIwhich are higher than the blood levels achieved in the same individualafter administration of the same dose of said AChEI given alone.

As set forth above, an nsPAChA is able to increase the maximum tolerateddose of an AChEI up to 4-fold; but, surprisingly, it has been found thatthe increase in AChEI blood concentrations in a subject treated with thensPAChA/AChEI combination and in whom the maximum tolerated doseincreased, for example, by two or three times the maximum toleratedAChEI dose reached with the AChEI alone, was much higher than expected,given that the increase in plasma concentrations with AChEIsadministered alone has been shown to be linearly dose-dependent withinthe dose ranges studied. This synergism was unexpected.

In addition, and even more surprisingly, it has been found that theadministration of overdoses of nsPAChAs (from more than twice to eighttimes the maximum dose used in the anticholinergic therapy) incombination with overdoses of AChEIs (from 2.5 to 7 times the maximumdose used in the treatment of Alzheimer type dementias) is safer thanthat with lower doses of nsPAChAs, the sole residual adverse effectbeing emesis which can be controlled by an appropriate dose of anantiemetic agent, and induces neuroprotection.

This synergism involves a great flexibility in the treatment ofneurodegeneration. In fact, according to the present invention, in thecase of a patient suffering from Alzheimer type dementia treated with agiven dose of AChEI, it is possible either to administer to said patientan overdose of nsPAChA, thus increasing the supply of acetylcholine tothe CNS of said patient without increasing the AChEI dose, or toadminister said patient an overdose of a nsPAChA by concurrentlyincrease the AChEI dose, thus safely supplying high amounts ofacetylcholine to the CNS of said patient thus assuring neuroprotection.

In this connection, the unexpected finding was that, in subjects treatedwith a nsPAChA/AChEI combination, the average plasma concentrations ofthe AChEI increased by 20% over the average plasma concentrationsmeasured after administration of the same dose of AChEI alone and, moresurprisingly, that in the same subjects and at the same nsPAChA dose insaid combination, the increase tends to be greater at higher AChEIdoses.

By chronic administration of the combination of nsPAChA/AChEI,overdoses, the potential, but heretofore barely, if at all, expressedneuroprotective action of the AChEIs is enabled and enhanced, thusallowing the neurodegenerative process to slow and therefore allowing todelay disease progression.

Moreover, it has been found that the combination of the synergisticaction of the nsPAChAs on AChE inhibition by the AChEIs, inducing higherthan expected AChEI blood levels and consequent increased concentrationsof acetylcholine in the CNS, with the concurrent, continuous opposingaction of the nsPAChAs (peripheral only) and of the AChEI (both centraland peripheral), allows for the theoretically infinite increase of thedoses of the nsPAChA/AChEI pair without untoward peripheralanticholinergic side effects, thus allowing the treatment of patientssuffering from dementia of Alzheimer type with very high doses of bothnsPAChA, i.e. from more than twice to 8 times the nsPAChA doses used inthe anticholinergic therapy, and AChEI, i.e. from 2.5 to 7 times theAChEI doses used in the treatment of Alzheimer type dementia.

Before the present invention, as noted above, doubling the dose ofrivastigmine by replacing immediate release tablets by skin patches,that blunt the peak blood levels, increased the amount of cognitiveimprovement in patients with Alzheimer's disease without significantlyincreasing side effects. According to the present invention, although ERformulations such as rivastigmine patches are also provided, this is notstrictly necessary because, by means of IR compositions of theinvention, very high blood levels of AChEI such as rivastigmine can beachieved without intolerable side effects.

It has also been found that a pharmaceutical composition comprising (a)an nsPAChA selected from the group consisting of1-methyl-4-[(2,2-diphenyl-2-n-propoxy)acetoxy]piperidine (propiverine)and pharmaceutically acceptable salts thereof, in an amount of from 15mg to 240 mg;3-(2-hydroxy-2,2-diphenylacetoxy)-spiro[bicyclo[3.2.1]octane-8,1′-pyrrolidin]-1′-ium(trospium) pharmaceutically acceptable salts, in an amount of from 20 mgto 480 mg; and3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium(glycopyrrolium) pharmaceutically acceptable salts, in an amount of from2 mg to 16 mg; and (b) a naAEA; in admixture with a pharmaceuticalcarrier, is able to increase the administered AChEI dose up to a factorof 7, thus allowing the safe overcome of the neuroprotective thresholdin the CNS of patients suffering from a dementia of Alzheimer type, andcombating neurodegeneration in patients, suffering from a dementia ofAlzheimer type, without appreciable signs of cholinergic and/or emeticadverse effects. The pharmaceutically acceptable salts of propiverineinclude the propiverine quaternary (C₁-C₄)alkylammonium halides, inparticular the1,1-dimethyl-4-[(2,2-diphenyl-2-n-propoxy)acetoxy]piperidininum chloride(methylpropiverinium chloride), the1,1-dimethyl-4-[(2,2-diphenyl-2-n-propoxy)acetoxy]piperidininum iodide(methylpropiverinium iodide) and, the1,1-dimethyl-4-[(2,2-diphenyl-2-n-propoxy)acetoxy]piperidininum bromide(methylpropiverinium bromide).

Even though, according to the previous findings, it is possible toincrease the AChEI doses by using low doses of nsPAChA in order toimprove the conditions of patients suffering from Alzheimer typedementia, with respect to the previous disclosures, the composition ofthe present invention has the advantage of (a) inducing a safe increaseof the AChEI blood levels by using AChEI doses which are at least 2.5times higher than the maximal recommended daily doses in the treatmentof Alzheimer type dementia; (b) safely increasing the AChEI doses up to7 times the maximum recommended doses and, consequently, to considerablyincrease AChEI concentrations in the CNS, thus enabling neuroprotection;(c) being administered once or twice a day; and (d), in contrast withthe fixed-dose combination described in WO 2009/120277 and WO2011/034568, allowing a correct administration of the AChEI in functionof the duration of action of said AChEI.

Additionally, even though, according to the previous findings, it ispossible to increase the AChEI doses by using low doses of nsPAChA inorder to improve the conditions of patients suffering from Alzheimertype dementia, it has been found that, by further increasing the dosesof nsPAChA up to 8 times the doses approved for anticholinergic therapy,it is possible (a) to induce neuroprotection by using AChEI doses whichare at least 2.5 times higher than the maximal recommended daily dosesin the treatment of Alzheimer type dementia; and (b) to safely increasethe AChEI doses up to 7 times, and even more, the maximum recommendeddaily doses with a consequent, considerable increase in acetylcholineconcentrations in the CNS.

In summary, high AChEI blood levels and consequent neuroprotection areobtained by a therapeutic method providing the administration ofcombined overdoses of both an nsPAChA and an ACHEI to a patientsuffering from Alzheimer type dementia. In this therapeutic method, thebest results are obtained when an antiemetic agent is added to thetherapy, said antiemetic agent having the sole effect of counteractingthe emetic effects of said AChEI overdose, thus improving patientcompliance of said therapy.

It has been found that the administration of solifenacin/antiemeticcomposition, when administered in combination with an AChEI, inparticular with donepezil, avoids the need for the usual prolongedtitration period of the AChEI dose because it allows the direct, safeadministration of the maximum recommended dose, and even of overdoses,of each AChEI to human subjects, including patients suffering fromAlzheimer type dementia.

High AChEI blood levels are safely obtained by a therapeutic methodproviding the administration of solifenacin/naAEA fixed combination andan AChEI overdose to a human subject, said subject possibly being apatient suffering from Alzheimer type dementia, thus allowing a safeadjustment of the AChEI doses of from 2.5 times to 7 times the maximumrecommended doses of said AChEI and inducing neuroprotection.

It has been found that the administration of an nsPAChA/AChEIcombination avoids the need for the usual prolonged titration period ofthe AChEI dose because it allows the direct, safe administration of themaximum recommended dose, and even of overdoses, of each AChEI to humansubjects, including patients suffering from Alzheimer type dementia,such that an increase of the maximum tolerated doses coincides with theincrease of the maximum recommended doses of each AChEI.

It has now been discovered that the nsPAChAs, when administered to ahuman being treated with a given dose of an AChEI, induce blood levelsof said AChEI which are higher than the blood levels achieved in thesame individual after administration of the same dose of said AChEIgiven alone.

As set forth above, an nsPAChA is able to increase the maximum tolerateddose of an AChEI up to 4-fold; but, surprisingly, it has been found thatAChEI blood levels in a subject treated with the nsPAChA/AChEIcombination, in whom the maximum tolerated AChEI dose increased, forexample, by two or three times the maximum tolerated dose reached withthe AChEI alone, are much higher than expected, given that the increasein plasma concentrations with AChEIs administered alone has been shownto be linearly dose-dependent within the dose ranges studied. Thissynergism was unexpected.

This synergism involves a great flexibility in the treatment ofneurodegeneration. In fact, according to the present invention, in thecase of a patient suffering from Alzheimer type dementia treated with agiven dose of AChEI, it is possible either to administer to said patientan overdose of nsPAChA, thus increasing the supply of concentrations ofAChEIs to the CNS of said patient without increasing the AChEI dose, orto administer said patient an overdose of a nsPAChA by concurrentlyincrease the AChEI dose, thus safely supplying high concentrations ofAChEIs to the CNS of said patient thus assuring neuroprotection.

Moreover, it has been found that the combination of the synergisticaction of the nsPAChAs on AChE inhibition by the AChEIs, inducing higherthan expected AChEI blood levels and consequent increased concentrationsof acetylcholine in the CNS, with the concurrent, continuous opposingaction of the nsPAChAs (peripheral only) and of the AChEI (both centraland peripheral), allows for the theoretically infinite increase of thedoses of the nsPAChA/AChEI pair without untoward peripheralanticholinergic side effects, thus allowing the treatment of patientssuffering from dementia of Alzheimer type with high doses of bothnsPAChA, i.e. from 100% to 8 times the nsPAChA doses used in theanticholinergic therapy, and AChEI, i.e. from 2.5 to 7 times, and evenmore, the AChEI doses used in the treatment of Alzheimer type dementia.

Thus, even though, according to the previous findings, it is possible toincrease the AChEI doses by using low doses of nsPAChA in order toimprove the conditions of patients suffering from Alzheimer typedementia, it has been found that, by further increasing the doses ofnsPAChA up to 8 times the doses approved for anticholinergic treatment,it is possible (a) to induce an increase of the AChEI blood levels byusing AChEI doses which are at least 2.5 times higher than the maximalrecommended daily doses in the treatment of Alzheimer type dementia; and(b) to safely increase the AChEI doses up to 7 times the maximumrecommended daily doses and, consequently, to considerably increaseAChEI concentrations in the CNS.

Before the present invention, as noted above, the replacement ofimmediate release tablets by skin patches, which diminished side effectsby blunting AChEI peak blood levels, allowed higher AChEI doses andproduced greater cognitive benefit in patients with Alzheimer-typedisease without inducing unacceptable side effects. Although the presentinvention can be applied to ER formulations such as patches, this is notreally necessary, since by means of the invention alone very high bloodAChEI levels can be achieved without intolerable side effects.

In summary, high AChEI blood levels are obtained by a therapeutic methodproviding the administration of combined high doses of both an nsPAChAand an ACHEI to a human subject, said subject possibly being a patientsuffering from Alzheimer type dementia. In this therapeutic method, thebest results are obtained when an antiemetic agent is added to thetherapy, said antiemetic agent having the sole effect of counteractingthe emetic effects of said AChEI overdose, thus improving patientcompliance to said therapy.

Before the present invention, as noted above, doubling the dose ofrivastigmine by replacing immediate release tablets by skin patches,that blunt the peak blood levels, increased the amount of cognitiveimprovement in patients with Alzheimer's disease without significantlyincreasing side effects. According to the present invention, although ERformulations such as rivastigmine patches are also provided, this is notstrictly necessary because, by means of IR compositions of theinvention, very high blood levels of AChEI such as rivastigmine can beachieved without intolerable side effects.

It has been found that the administration of an nsPAChA/AChEIcombination avoids the need for the usual prolonged titration period ofthe AChEI dose because it allows the direct, safe administration of themaximum recommended dose, and even of overdoses, of each AChEI to humansubjects, including patients suffering from Alzheimer type dementia,such that an increase of the maximum tolerated doses coincides with theincrease of the maximum recommended doses of each AChEI.

Moreover, it has been found that the combination of the synergisticaction of the nsPAChAs on AChE inhibition by the AChEIs, inducing higherthan expected AChEI blood levels and consequent increased concentrationsof AChEIs in the CNS, with the concurrent, continuous opposing action ofthe nsPAChAs (peripheral only) and of the AChEI (both central andperipheral), allows for the theoretically infinite increase of the dosesof the nsPAChA/AChEI pair without untoward peripheral anticholinergicside effects, allows the treatment of patients suffering from dementiaof Alzheimer type with very high doses of both nsPAChA, i.e. from morethan twice to 8 times the nsPAChA doses used in the anticholinergictherapy, and AChEI, i.e. from 2.5 to 7 times the AChEI doses used in thetreatment of Alzheimer type dementia.

It has also been found that a pharmaceutical composition comprising (a)an nsPAChA selected from the group consisting of(1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-iso-quinolinecarboxylate (solifenacin) andpharmaceutically acceptable salts and compounds thereof, in an amountwhich is equivalent to from 10 mg to 80 mg of solifenacin succinate; and(b) a naAEA; in admixture with a pharmaceutical carrier, is able toincrease the administered AChEI dose up to a factor of 7, thus allowingthe safe overcome of the neuroprotective threshold in the CNS ofpatients suffering from a dementia of Alzheimer type, and combatingneurodegeneration in patients, suffering from a dementia of Alzheimertype, without appreciable signs of cholinergic and/or emetic adverseeffects. The pharmaceutically acceptable salts and compounds ofsolifenacin include the quaternary ammonium salts, in particular themethylchloride (methylsolifenacinium chloride), the methyliodide(methylsolifenacinium iodide) and the methylbromide(methylsolifenacinium bromide).

Thus, even though, according to the previous findings, it is possible toincrease the AChEI doses by using low doses of nsPAChA in order toimprove the conditions of patients suffering from Alzheimer typedementia, with respect to the previous disclosures the composition ofthe present invention has the advantage of (a) inducing a safe increaseof AChEI blood levels with AChEI doses which are at least 2.5 timeshigher than the maximal recommended daily doses in the treatment ofAlzheimer type dementia; (b) safely increasing the AChEI doses up to 7times the maximum recommended doses and, consequently, to considerablyincrease AChEI concentrations in the CNS, thus allowing forneuroprotection; (c) being administered once per day; and (d), incontrast with the fixed-dose combination described in WO 2009/120277 andWO 2011/034568, allowing a correct administration of the AChEI infunction of the duration of action of said AChEI.

In summary, high AChEI blood levels are safely obtained by a therapeuticmethod providing the administration of solifenacin/naAEA fixedcombination and an AChEI overdose to a human subject, said subjectpossibly being a patient suffering from Alzheimer type dementia, thusallowing a safe adjustment of the AChEI doses of from 2.5 times to 7times the maximum recommended doses of said AChEI and inducingneuroprotection.

It has been found that the administration of solifenacin/antiemeticcomposition, when administered in combination with an AChEI, inparticular with donepezil, avoids the need for the usual prolongedtitration period of the AChEI dose because it not only allows thedirect, safe administration of the maximum recommended dose of theAChEI, but also of even much higher doses, of each AChEI to humansubjects, including patients suffering from Alzheimer type dementia.

One aspect of the present invention is related to a pharmaceuticalcomposition comprising a nsPAChA selected from the group consisting ofpropiverine and pharmaceutically acceptable salts thereof, in an amountwhich is equivalent to from 15 mg to 120 mg of propiverinehydrochloride; trospium pharmaceutically acceptable salts, in an amountwhich is equivalent to from 20 mg to 480 mg of trospium chloride; andglycopyrrolium pharmaceutically acceptable salts, in an amount which isequivalent to from 2 mg to 16 mg of glycopyrronium bromide; and (b) anon-anticholinergic antiemetic agent (naAEA); in admixture with apharmaceutical carrier.

In one embodiment the composition is such that the nsPAChA ispropiverine hydrochloride, in an amount of from 31 mg to 240 mg. Inanother embodiment, the composition is such that nsPAChA is trospiumchloride, in an amount of from 61 mg to 480 mg. In another embodiment,the composition is such that nsPAChA is glycopyrrolium bromide, in anamount of from 4.1 mg to 16 mg. In another embodiment, the compositionis such that Component (b) is a naAEA selected from the group consistingof (b1) 5HT3-antagonists, (b2) DA-antagonists, (b3) H1-antagonists, (b4)cannabinoids, (b5) aprepitant.

In another embodiment, the composition is such that naAEA is selectedfrom the group consisting of alosetron and pharmaceutically acceptablesalts and solvates thereof, in an amount (in alosetron) of from 0. 5 mgto 3 mg; dolasetron and pharmaceutically acceptable salts thereof, in anamount (in dolasetron) of from 50 mg to 300 mg; granisetron andpharmaceutically acceptable salts thereof, in an amount (in granisetron)of from 1 mg to 3 mg; ondansetron and pharmaceutically acceptable saltsand solvates thereof, in an amount (in ondansetron) of from 4 mg to 24mg; tropisetron and pharmaceutically acceptable salts thereof, in anamount (in tropisetron) of from 5 mg to 15 mg; domperidone andpharmaceutically acceptable salts and solvates thereof, in an amount (indomperidone) of from 10 mg to 30 mg; metoclopramide and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in metoclopramide)of from 10 mg to 30 mg; bromopride and pharmaceutically acceptable saltsand solvates thereof, in an amount (in bromopride) of from 10 mg to 30mg; clebopride and pharmaceutically acceptable salts thereof, in anamount (in clebopride) of from 0.5 mg to 1.5 mg; and aprepitant, in anamount of from 40 mg to 375 mg.

In yet another embodiment, the composition is such that Component (b) isa naAEA selected from the group consisting of alosetron andpharmaceutically acceptable salts and solvates thereof in an amount (inalosetron) of from 0.5 mg to 3 mg; dolasetron and pharmaceuticallyacceptable salts and solvates thereof in an amount (in dolasetron) offrom 50 mg to 300 mg; granisetron and pharmaceutically acceptable saltsand solvates thereof in an amount (in granisetron) of from 1 mg to 3 mg;ondansetron and pharmaceutically acceptable salts and solvates thereofin an amount (in ondansetron) of from 4 mg to 24 mg; tropisetron andpharmaceutically acceptable salts and solvates thereof in an amount offrom 5 mg to 15 mg; domperidone and pharmaceutically acceptable saltsand solvates thereof, in an amount (in domperidone) of from 10 mg to 30mg; and metoclopramide and pharmaceutically acceptable salts andsolvates thereof, in an amount (in metoclopramide) of from 10 mg to 30mg.

In another embodiment, the composition is such that naAEA is selectedfrom the group consisting of alosetron and pharmaceutically acceptablesalts and solvates thereof, in an amount (in alosetron) of from 0. 5 mgto 3 mg; granisetron and pharmaceutically acceptable salts and solvatesthereof in an amount (in granisetron) of from 1 mg to 3 mg; ondansetronand pharmaceutically acceptable salts and solvates thereof, in an amount(in ondansetron) of from 4 mg to 24 mg; tropisetron and pharmaceuticallyacceptable salts thereof, in an amount (in tropisetron) of from 5 mg to15 mg; domperidone and pharmaceutically acceptable salts and solvatesthereof, in an amount (in domperidone) of from 10 mg to 30 mg;metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in an amount (in metoclopramide) of from 10 mg to 30 mg.

In another embodiment, the composition is such that nsPAChA Component(a) is selected from the group consisting of propiverine andpharmaceutically acceptable salts thereof, in an amount which isequivalent to from 15 mg to 120 mg of propiverine hydrochloride;trospium pharmaceutically acceptable salts, in an amount which isequivalent to from 20 mg to 480 mg of trospium chloride; andglycopyrrolium pharmaceutically acceptable salts, in an amount which isequivalent to from 2 mg to 16 mg of glycopyrronium bromide; and (b) andsaid naAEA is selected from the group consisting of alosetron andpharmaceutically acceptable salts and solvates thereof, in an amount (inalosetron) of from 0. 5 mg to 3 mg; granisetron and pharmaceuticallyacceptable salts and solvates thereof in an amount (in granisetron) offrom 1 mg to 3 mg; ondansetron and pharmaceutically acceptable salts andsolvates thereof, in an amount (in ondansetron) of from 4 mg to 24 mg;tropisetron and pharmaceutically acceptable salts thereof, in an amount(in tropisetron) of from 5 mg to 15 mg; domperidone and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in domperidone) offrom 10 mg to 30 mg; metoclopramide and pharmaceutically acceptablesalts and solvates thereof, in an amount (in metoclopramide) of from 10mg to 30 mg.

The present invention is also related to a method for inducingneuroprotection, thus combating neurodegeneration, and consequentlyslowing disease progression in a patient suffering from a dementia ofthe Alzheimer type, which comprises administering to said patient anAChEI daily dose which is at least 2.5, up to 7 times the maximumrecommended dose daily of said AChEI used in the treatment of Alzheimertype dementias, in combination with a pharmaceutical compositioncomprising (a) an nsPAChA selected from the group consisting ofpropiverine and pharmaceutically acceptable salts thereof, in an amountwhich is equivalent to from 15 mg to 120 mg of propiverinehydrochloride; trospium pharmaceutically acceptable salts, in an amountwhich is equivalent to from 20 mg to 480 mg of trospium chloride; andglycopyrrolium pharmaceutically acceptable salts, in an amount which isequivalent to from 2 mg to 16 mg of glycopyrronium bromide; and (b) anon-anticholinergic antiemetic agent (naAEA); in admixture with apharmaceutical carrier.

The compositions of the present invention can be used for inducingneuroprotection, thus combating neurodegeneration, in a patientsuffering from a dementia of Alzheimer type, in combination with anAChEI.

Another aspect of the present invention is related to a pharmaceuticalcomposition comprising an nsPAChA selected from the group consisting of(1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate and pharmaceuticallyacceptable salts and compounds thereof, in an amount which is equivalentto from 10 mg to 80 mg of solifenacin succinate; and (b) anon-anticholinergic antiemetic agent (naAEA); in admixture with apharmaceutical carrier.

In one embodiment according to the above aspect of the presentinvention, the composition is such that nsPAChA is present in an amountwhich is equivalent to from 11 mg to 80 mg of solifenacin succinate. Inanother embodiment, the composition is such that nsPAChA is present inan amount which is equivalent to from 15 mg to 80 mg of solifenacinsuccinate. In yet another embodiment, the composition is such thatnsPAChA is present in an amount which is equivalent to from 21 mg to 80mg of solifenacin succinate.

A composition according to the present invention is such that Component(b) is a naAEA selected from the group consisting of (b1)5HT3-antagonists, (b2) DA-antagonists, (b3) H1-antagonists, (b4)cannabinoids, (b5) aprepitant.

In another embodiment, the composition is such that Component (b) isselected from the group consisting of alosetron and pharmaceuticallyacceptable salts and solvates thereof in an amount (in alosetron) offrom 0.5 mg to 3 mg; dolasetron and pharmaceutically acceptable saltsand solvates thereof in an amount (in dolasetron) of from 50 mg to 300mg; granisetron and pharmaceutically acceptable salts and solvatesthereof in an amount (in granisetron) of from 1 mg to 3 mg; ondansetronand pharmaceutically acceptable salts and solvates thereof in an amount(in ondansetron) of from 4 mg to 24 mg; tropisetron and pharmaceuticallyacceptable salts and solvates thereof in an amount of from 5 mg to 15mg; domperidone and pharmaceutically acceptable salts and solvatesthereof, in an amount (in domperidone) of from 10 mg to 30 mg; andmetoclopramide and pharmaceutically acceptable salts and solvatesthereof, in an amount (in metoclopramide) of from 10 mg to 30 mg.

In yet another embodiment, the composition is such that naAEA isselected from the group consisting of alosetron and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in alosetron) offrom 0. 5 mg to 3 mg; dolasetron and pharmaceutically acceptable saltsthereof, in an amount (in dolasetron) of from 50 mg to 300 mg;granisetron and pharmaceutically acceptable salts thereof, in an amount(in granisetron) of from 1 mg to 3 mg; ondansetron and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in ondansetron) offrom 4 mg to 24 mg; tropisetron and pharmaceutically acceptable saltsthereof, in an amount (in tropisetron) of from 5 mg to 15 mg;domperidone and pharmaceutically acceptable salts and solvates thereof,in an amount (in domperidone) of from 10 mg to 30 mg; metoclopramide andpharmaceutically acceptable salts and solvates thereof, in an amount (inmetoclopramide) of from 10 mg to 30 mg; bromopride and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in bromopride) offrom 10 mg to 30 mg; clebopride and pharmaceutically acceptable saltsthereof, in an amount (in clebopride) of from 0.5 mg to 1.5 mg; andaprepitant, in an amount of from 40 mg to 375 mg.

In another embodiment, the composition is such that naAEA is selectedfrom the group consisting of alosetron and pharmaceutically acceptablesalts and solvates thereof, in an amount (in alosetron) of from 0. 5 mgto 3 mg; granisetron and pharmaceutically acceptable salts and solvatesthereof in an amount (in granisetron) of from 1 mg to 3 mg; ondansetronand pharmaceutically acceptable salts and solvates thereof, in an amount(in ondansetron) of from 4 mg to 24 mg; tropisetron and pharmaceuticallyacceptable salts thereof, in an amount (in tropisetron) of from 5 mg to15 mg; domperidone and pharmaceutically acceptable salts and solvatesthereof, in an amount (in domperidone) of from 10 mg to 30 mg;metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in an amount (in metoclopramide) of from 10 mg to 30 mg.

In another embodiment, the composition is such that nsPAChA Component(a) is present in an amount which is equivalent to from 11 mg to 80 mgof solifenacin succinate and said naAEA is selected from the groupconsisting of alosetron and pharmaceutically acceptable salts andsolvates thereof, in an amount (in alosetron) of from 0. 5 mg to 3 mg;granisetron and pharmaceutically acceptable salts and solvates thereofin an amount (in granisetron) of from 1 mg to 3 mg; ondansetron andpharmaceutically acceptable salts and solvates thereof, in an amount (inondansetron) of from 4 mg to 24 mg; tropisetron and pharmaceuticallyacceptable salts thereof, in an amount (in tropisetron) of from 5 mg to15 mg; domperidone and pharmaceutically acceptable salts and solvatesthereof, in an amount (in domperidone) of from 10 mg to 30 mg;metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in an amount (in metoclopramide) of from 10 mg to 30 mg.

In yet another embodiment, the composition is such that nsPAChAComponent (a) is present in an amount which is equivalent to from 15 mgto 80 mg of solifenacin succinate and said naAEA Component (b) isselected from the group consisting of alosetron and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in alosetron) offrom 0. 5 mg to 3 mg; granisetron and pharmaceutically acceptable saltsand solvates thereof in an amount (in granisetron) of from 1 mg to 3 mg;ondansetron and pharmaceutically acceptable salts and solvates thereof,in an amount (in ondansetron) of from 4 mg to 24 mg; tropisetron andpharmaceutically acceptable salts thereof, in an amount (in tropisetron)of from 5 mg to 15 mg; domperidone and pharmaceutically acceptable saltsand solvates thereof, in an amount (in domperidone) of from 10 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in an amount (in metoclopramide) of from 10 mg to 30 mg.

In another embodiment, the composition is such that nsPAChA Component(a) is present in an amount which is equivalent to from 21 mg to 80 mgof solifenacin succinate and said naAEA Component (b) is selected fromthe group consisting of alosetron and pharmaceutically acceptable saltsand solvates thereof, in an amount (in alosetron) of from 0. 5 mg to 3mg; granisetron and pharmaceutically acceptable salts and solvatesthereof in an amount (in granisetron) of from 1 mg to 3 mg; ondansetronand pharmaceutically acceptable salts and solvates thereof, in an amount(in ondansetron) of from 4 mg to 24 mg; tropisetron and pharmaceuticallyacceptable salts thereof, in an amount (in tropisetron) of from 5 mg to15 mg; domperidone and pharmaceutically acceptable salts and solvatesthereof, in an amount (in domperidone) of from 10 mg to 30 mg;metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in an amount (in metoclopramide) of from 10 mg to 30 mg.

The present invention is related to a method for inducingneuroprotection, thus combating neurodegeneration, and consequentlyslowing disease progression in a patient suffering from a dementia ofthe Alzheimer type, which comprises administering to said patient anAChEI daily dose which is at least 2.5, up to 7 times the maximumrecommended dose daily of said AChEI used in the treatment of Alzheimertype dementias, in combination with a pharmaceutical compositioncomprising an nsPAChA selected from the group consisting of(1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate and pharmaceuticallyacceptable salts and compounds thereof, in an amount which is equivalentto from 10 mg to 80 mg of solifenacin succinate; and (b) anon-anticholinergic antiemetic agent (naAEA); in admixture with apharmaceutical carrier.

The composition of the present invention can be used for inducingneuroprotection, thus combating neurodegeneration, in a patientsuffering from a dementia of Alzheimer type, in combination with anAChEI.

Another aspect of the present invention is related to a method forinducing neuroprotection in a patient suffering from an Alzheimer typedementia, which comprises administering said patient an AChEI dose whichis at least 2.5, up to 7 times the maximum recommended dose used in thetreatment of Alzheimer type dementias, in combination with an nsPAChAdose which is more than twice, up to 8 times the dose used in theanticholinergic therapy.

In one embodiment, the method is such that AChEI is selected from thegroup consisting of(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one(donepezil) and its pharmaceutically acceptable salts,(S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate(rivastigmine) and its pharmaceutically acceptable salts,4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol(galantamine) and its pharmaceutically acceptable salts; and(1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0^(2,7)]trideca-2(7),3,10-trien-5-one(Huperzine A).

In one embodiment, method of the present invention is such that AChEI isdonepezil or a pharmaceutically acceptable salt thereof, at a daily doseof from 25 mg to 151 mg. In another embodiment, the method of thepresent invention is such that AChEI is rivastigmine or apharmaceutically acceptable salt thereof, at a daily dose of from 30 mgto 93 mg. In another embodiment, the method of is such that AChEI isgalantamine or a pharmaceutically acceptable salt thereof, at a dose offrom 60 mg to 224 mg. The method of the present invention is such thatAChEI is huperzine A, at a dose of from 0.45 mg to 4.8 mg.

In another embodiment, the method of the present invention is such thatnsPAChA is selected from the group consisting of(1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (solifenacin) andpharmaceutically acceptable salt and compounds thereof,1-methyl-4-[(2,2-diphenyl-2-n-propoxy)acetoxy]piperidine (propiverine)and pharmaceutically acceptable salts thereof,3-(2-hydroxy-2,2-diphenylacetoxy)-spiro[bicyclo[3.2.1]octane-8,1′-pyrrolidin]-1′-ium(trospium) pharmaceutically acceptable salts, and3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium(glycopyrrolium) pharmaceutically acceptable salts.

In another embodiment, the method of the present invention is such thatnsPAChA is administered at a daily dose which is from more than 200% to800% the dose used in the anticholinergic therapy. In one embodiment,the method of the present invention is such that nsPAChA is trospiumchloride, in an IR formulation administered at daily a dose of from morethan 80 mg to 360 mg. In another embodiment, the method of the presentinvention is such that nsPAChA is trospium chloride, in an ERformulation administered at a daily dose of from more than 120 mg to 480mg.

The method according to the present invention also includes nsPAChA aspropiverine hydrochloride, in an IR or ER formulation administered at adose of from more than 60 mg to 240 mg. In one embodiment, the method ofpresent invention is such that nsPAChA is solifenacin succinate, in anIR formulation administered at a daily dose of from more than 20 mg to80 mg. Also, the method of the present invention is such that AChEI isdonepezil hydrochloride, administered at a daily dose of from 25 mg to151 mg and said nsPAChA is solifenacin succinate, administered at adaily dose of from 21 mg to 80 mg.

In one embodiment, the method of the present invention is such thatAChEI is galantamine hydrobromide, administered at a daily dose (ingalantamine) of from 60 mg to 224 mg, and said nsPAChA is propiverine,as hydrochloride, administered at a daily dose of from 61 mg to 240 mg.In another embodiment, the method of the present invention is such thatAChEI is rivastigmine, as hydrogen tartrate, administered at a dailydose of from 30 mg to 93 mg, and said nsPAChA is selected from the groupconsisting of trospium chloride, administered at a daily dose of from 80mg to 480 mg; propiverine, as hydrochloride, administered at a dailydose of from 61 mg to 240 mg; and solifenacin succinate, administered ata daily dose of from 21 mg to 80 mg.

Another aspect of the present invention is related to a pharmaceuticalcomposition comprising, as an active ingredient, an nsPAChA selectedfrom the group consisting of solifenacin and pharmaceutically acceptablesalts thereof, propiverine and pharmaceutically acceptable saltsthereof, glycopyrronium pharmaceutically acceptable salts and trospiumpharmaceutically acceptable salts, in an amount which is from more than200% to 800% the maximum amount of said nsPAChA contained incompositions indicated for the anticholinergic therapy, for use forinducing neuroprotection and combating neurodegeneration in a patientsuffering from a dementia of Alzheimer type who is treated with an AChEIdose which is from 250% to 700% the maximum recommended dose of saidAChEI.

In one embodiment, the composition of the present invention is such thatnsPAChA is selected from the group consisting of trospium chloride, inan amount of from more than 40 mg to 480 mg; solifenacin succinate, inan amount of from more than 20 mg to 80 mg; and propiverinehydrochloride, in an amount of from more than 30 mg to 240 mg. Inanother embodiment, the composition of the present invention is suchthat nsPAChA selected from the group consisting of glycopyrroliumbromide, in an amount of from 4.2 mg to 16 mg, in admixture with apharmaceutical carrier in an IR formulation; trospium chloride in anamount of from 42 mg to 160 mg, in admixture with a pharmaceuticalcarrier in an IR formulation; trospium chloride in an amount of from 126mg to 480 mg, in admixture with a pharmaceutical carrier, in an ERformulation; solifenacin succinate in an amount of from 21 mg to 80 mg,in admixture with a pharmaceutical carrier in an IR formulation;propiverine hydrochloride in an amount of from 31.5 mg to 120 mg, inadmixture with a pharmaceutical carrier in an IR formulation; andpropiverine hydrochloride in an amount of from 61 mg to 240 mg, inadmixture with a pharmaceutical carrier in an ER formulation.

In another embodiment, the composition of the present invention is suchthat nsPAChA is selected from the group consisting of glycopyrroniumbromide in an amount of from 4.5 mg to 16 mg, in admixture with apharmaceutical carrier in an IR formulation; trospium chloride in anamount of from 60 mg to 160 mg, in admixture with a pharmaceuticalcarrier in an IR formulation; solifenacin succinate in an amount of from25 mg to 80 mg, in admixture with a pharmaceutical carrier in an IRformulation; and propiverine hydrochloride in an amount of from 31.5 mgto 120 mg, in admixture with a pharmaceutical carrier in an IRformulation. In another embodiment, the composition of the presentinvention can be used for inducing neuroprotection and combatingneurodegeneration in a patient suffering from an Alzheimer type dementiawho is treated with an AChEI dose which is from 2.5 to 7 times higherthan the maximum recommended dose of said AChEI.

The present invention is also related to a method for increasing AChEIblood concentrations in a human being, which comprises administeringsaid human being a nsPAChA dose which is at least equal to, up to 8times the dose used in the anticholinergic therapy, in combination withan AChEI dose which is at least 2.5, times, up to 7 times the dose ofsaid AChEI used in the treatment of Alzheimer type dementias. In oneembodiment, the method of the present invention is such that human beingis a patient suffering from an Alzheimer type dementia and saidcombination is administered chronically.

The method of present invention is such that AChEI is selected from thegroup consisting of(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one(donepezil) and its pharmaceutically acceptable salts,(S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate(rivastigmine) and its pharmaceutically acceptable salts,4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol(galantamine) and its pharmaceutically acceptable salts; and(1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0^(2,7)]trideca-2(7),3,10-trien-5-one(Huperzine A).

In one embodiment, the method of the present invention is such thatAChEI is donepezil or a pharmaceutically acceptable salt thereof, at adaily dose of from 25 mg to 151 mg. In another embodiment, the method ofthe present invention is such that AChEI is rivastigmine or apharmaceutically acceptable salt thereof, at a daily dose of from 30 mgto 126 mg.

In another embodiment, the method of the present invention is such thatAChEI is galantamine or a pharmaceutically acceptable salt thereof, at adaily dose of from 60 mg to 224 mg. In yet another embodiment, themethod of the present invention is such that AChEI is huperzine A, at adaily dose of from 0.45 mg to 4.8 mg. In another embodiment, the methodof the present invention is such that nsPAChA is selected from the groupconsisting of (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (solifenacin) andpharmaceutically acceptable salt and compounds thereof,1-methyl-4-[(2,2-diphenyl-2-n-propoxy)acetoxy]piperidine (propiverine)and pharmaceutically acceptable salts thereof,3-(2-hydroxy-2,2-diphenylacetoxy)-spiro[bicyclo[3.2.1]octane-8,1′-pyrrolidin]-1′-ium(trospium) pharmaceutically acceptable salts, and3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium(glycopyrrolium) pharmaceutically acceptable salts.

In yet another embodiment, the method of the present invention is suchthat nsPAChA is trospium chloride, in an IR formulation administered ata daily dose of from 40 mg to 360 mg. In another embodiment, the methodis such that nsPAChA is trospium chloride, in an ER formulationadministered at a daily dose of from 60 mg to 480 mg. In anotherembodiment, the method is such that nsPAChA is propiverinehydrochloride, in an IR or ER formulation administered at a daily doseof from 30 mg to 120 mg. In another embodiment, the method is such thatnsPAChA is solifenacin succinate, in an IR formulation administered at adaily dose of from 10 mg to 80 mg.

In another embodiment, the method of the present invention is such thatAChEI is donepezil hydrochloride, administered at a daily dose of from25 to 60 mg and said nsPAChA is solifenacin succinate, in an IRformulation administered at a daily dose of from 10 mg to 20 mg. In yetanother embodiment, the method according to the present invention issuch that AChEI is galantamine hydrobromide, administered at a dailydose of from 60 to 168 mg, in an IR or ER formulation and said nsPAChAis propiverine hydrochloride, in an IR or, respectively, ER formulationadministered at a daily dose of from 30 mg to 120 mg. In one embodiment,the method according to the present invention is such that doses of boththe AChEI and the nsPAChA are in IR formulations.

The present invention is also related to a pharmaceutical compositioncomprising, as an active ingredient, an nsPAChA selected from the groupconsisting of solifenacin and pharmaceutically acceptable salts thereof,propiverine and pharmaceutically acceptable salts thereof,glycopyrronium pharmaceutically acceptable salts and trospiumpharmaceutically acceptable salts, in an amount which is from 100% to800% the maximum amount of said nsPAChA contained in compositionsindicated for the anticholinergic therapy, for use for increasing theAChEI blood levels in a human treated with an AChEI dose which is from250% to 700% the maximum tolerated dose and maximum recommended dose ofsaid AChEI.

In one embodiment, the composition is such that nsPAChA activeingredient is selected from the group consisting of glycopyrroliumbromide, in an amount of from 2 mg to 16 mg, in admixture with apharmaceutical carrier in an IR formulation; trospium chloride in anamount of from 20 mg to 160 mg in an IR formulation; trospium chloridein an amount of from 60 mg to 480 mg in an ER formulation; solifenacinsuccinate in an amount of from 10 mg to 20 mg in an IR formulation;propiverine hydrochloride in an amount of from 15 mg to 120 mg in an IRformulation; and propiverine hydrochloride in an amount of from 30 mg to240 mg in an ER formulation.

DETAILED DESCRIPTION OF THE INVENTION

I. First Aspect of the Present Invention

In a first aspect, the present invention provides a pharmaceuticalcomposition comprising a nsPAChA selected from the group consisting ofpropiverine and pharmaceutically acceptable salts thereof, trospiumpharmaceutically acceptable salts and glycopyrrolium pharmaceuticallyacceptable salts; and a naAEA, in admixture with a pharmaceuticalcarrier.

More particularly, it is an object of the present invention to provide acomposition comprising (a) an nsPAChA selected from the group consistingof 1-methyl-4-[(2,2-diphenyl-2-n-propoxy)acetoxy]piperidine(propiverine) and pharmaceutically acceptable salts thereof, in anamount which is equivalent to from 15 mg to 240 mg of propiverinehydrochloride;3-(2-hydroxy-2,2-diphenylacetoxy)-spiro[bicyclo[3.2.1]octane-8,1′-pyrrolidin]-1′-ium(trospium) pharmaceutically acceptable salts, in an amount which isequivalent to from 20 mg to 480 mg of trospium chloride; and3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium(glycopyrrolium) pharmaceutically acceptable salts, in an amount whichis equivalent to from 2 mg to 16 mg of glycopyrrolium bromide; and (b) anaAEA; in admixture with a pharmaceutical carrier.

Propiverine and pharmaceutically acceptable salts thereof, in particularits hydrochloride, are described in DD 106643, CN 1285348, CN102218063(A), KR 2005-0011138, KR 2005-0011139, KR20110111782 (A) and inWO 2011/114195. The propiverine quaternary salts, i.e. the (C₁-C₄)alkylpropiverinium halides may be prepared by reacting1-methyl-4-[(2,2-diphenyl-2-propoxy)acetoxy]piperidine (propiverinebase) with a (C₁-C₄)alkyl halide (chloride, bromide or iodide), thepropiverine base starting material being also obtained as crude productas described in WO 2011/114195 or by hydrolysis of propiverinehydrochloride, which is an easily available commercial product alsoobtainable for example as described in DD 106643, CN 1285348, CN102218063(A) KR 2005-0011138, KR 2005-0011139, KR20110111782 (A) or inthe aforesaid WO 2011/114195. In practice, an aqueous suspension ofpropiverine hydrochloride is treated with an inorganic base and crudepropiverine base is recovered by extraction from an organic solvent andevaporation of the solvent; and the residue is treated with a(C₁-C₄)alkyl (preferably methyl) halide (chloride, bromide or iodide) inan alcoholic solution and the1-alkyl-1-methyl-4-[(2,2-diphenyl-2-propoxy)acetoxy]piperidinium halidewhich precipitates is isolated.

Trospium chloride is described in U.S. Pat. No. 3,480,626 and otherpharmaceutically acceptable salts thereof are cited in US 2006/0293356.

Glycopyrronium pharmaceutical acceptable salts, in particular thebromide, are obtainable according to U.S. Pat. No. 2,956,062.

Component (a) is a nsPAChA selected from the group consisting ofpropiverine and pharmaceutically acceptable salts thereof, in an amountwhich is equivalent to from 15 mg to 120 mg of propiverinehydrochloride; trospium pharmaceutically acceptable salts, in an amountwhich is equivalent to from 20 mg to 480 mg of trospium chloride; andglycopyrrolium pharmaceutically acceptable salts, in an amount which isequivalent to from 2 mg to 16 mg of glycopyrronium bromide

Advantageously, the nsPAChA Component (a) of the composition is selectedfrom the group consisting of propiverine hydrochloride, in an amount offrom 15 mg to 240 mg, advantageously from 30 mg to 240 mg, preferablyfrom 31 mg to 240 mg; trospium chloride, in an amount of from 20 mg to480 mg, advantageously from 40 mg to 480 mg, preferably from 61 mg to480 mg; and glycopyrrolium bromide, in an amount of from 2 mg to 16 mg,advantageously from 4 mg to 16 mg, preferably from 4.1 to 16 mg.

According to a preferred embodiment, the nsPAChA Component (a) isselected from the group consisting of propiverine hydrochloride in anamount of from 15 mg to 120 mg, advantageously from 30 mg to 120 mg,preferably from 31 mg to 120 mg, most preferably from 31 mg to 90 mg, inadmixture with a pharmaceutical carrier in an IR formulation;propiverine hydrochloride in an amount of from 30 mg to 240 mg,advantageously from 60 mg to 240 mg, preferably from 61 mg to 240 mg,most preferably from 61 mg to 180 mg, in admixture with a pharmaceuticalcarrier in an ER formulation; trospium chloride in an amount of from 20mg to 180 mg, from 40 mg to 160 mg preferably from 61 mg to 160 mg, mostpreferably from 61 mg to 140 mg, in admixture with a pharmaceuticalcarrier in an IR formulation; trospium chloride in an amount of from 60mg to 480 mg, advantageously from 120 mg to 480 mg, preferably from 121mg to 480 mg, most preferably from 61 mg to 360 mg, in admixture with apharmaceutical carrier in an ER formulation; and glycopyrrolium bromide,in an amount of from 2 mg to 16 mg, advantageously from 4 mg to 16 mg,preferably from 4.1 to 16 mg, most preferably from 4.1 mg to 12 mg, inadmixture with a pharmaceutical carrier in an IR formulation.

The naAEA Component (b) is present in an amount of from 100% to 300% ofthe amount of the said naAEA contained as a sole active ingredient inthe currently used brand or generic drugs.

According to a preferred embodiment, said Component (b) is anon-anticholinergic antiemetic agent selected from the group consistingof (b1) 5HT3-antagonists, (b2) DA-antagonists, (b3) H1-antagonists, (b4)cannabinoids, (b5) aprepitant. Typical naAEAs of the above classes areillustrated in WO 2011/034568.

An advantageous Component (b) is selected from the group consisting ofalosetron and pharmaceutically acceptable salts and solvates thereof, inparticular the hydrochloride, in an amount (in alosetron) of from 0.5 mgto 3 mg; dolasetron and pharmaceutically acceptable salts and solvatesthereof, in particular the mesylate, in an amount (in dolasetron) offrom 50 mg to 300 mg; granisetron and pharmaceutically acceptable saltsand solvates thereof, in particular the hydrochloride, in an amount (ingranisetron) of from 1 mg to 3 mg; ondansetron and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloridedihydrate, in an amount (in ondansetron) of from 4 mg to 24 mg;tropisetron and pharmaceutically acceptable salts and solvates thereof,in particular the hydrochloride, in an amount of from 5 mg to 15 mg;domperidone and pharmaceutically acceptable salts and solvates thereof,in an amount (in domperidone) of from 10 mg to 30 mg; haloperidol, in anamount of from 1 mg to 30 mg; chlorpromazine and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in chlorpromazine) of from 25 mg to 75 mg;prochlorperazine and pharmaceutically acceptable salts and solvatesthereof, in particular the dimaleate, in an amount (in prochlorperazine)of from 5 mg to 30 mg; metoclopramide and pharmaceutically acceptablesalts and solvates thereof, in particular the monohydrochloridemonohydrate, in an amount (in metoclopramide) of from 10 mg to 30 mg;bromopride and pharmaceutically acceptable salts and solvates, inparticular the monohydrochloride and the dihydrochloride monohydrate, inan amount (in bromopride) of from 10 mg to 30 mg; clebopride andpharmaceutically acceptable salts and solvates thereof, in particularthe hydrogen malate and the hydrochloride monohydrate, in an amount (inclebopride) of from 0. 5 mg to 1.5 mg; levosulpiride, in an amount offrom 25 mg to 300 mg; alizapride and pharmaceutically acceptable saltsthereof, in particular the hydrochloride, in an amount (in alizapride)of from 50 mg to 150 mg; trimethobenzamide and pharmaceuticallyacceptable salts thereof such as the monohydrochloride, in an amount (intrimethobenzamide) of from 300 mg to 900 mg; meclizine andpharmaceutically acceptable salts and solvates thereof, in an amount (inmeclizine) of from 13 mg to 150 mg; promethazine and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in prometazine) of from 25 mg to 150 mg; dronabinol in anamount of from 2.5 mg to 60 mg; nabilone, in an amount of from 2 mg to12 mg; and aprepitant, in an amount of from 40 mg to 375 mg.

An advantageous non-anticholinergic antiemetic agent Component (b) insaid pharmaceutical composition is selected from the group consisting ofalosetron and pharmaceutically acceptable salts and solvates thereof, inan amount (in alosetron) of from 0. 5 mg to 3 mg; dolasetron andpharmaceutically acceptable salts thereof, in an amount (in dolasetron)of from 50 mg to 300 mg; granisetron and pharmaceutically acceptablesalts thereof, in an amount (in granisetron) of from 1 mg to 3 mg;ondansetron and pharmaceutically acceptable salts and solvates thereof,in an amount (in ondansetron) of from 4 mg to 24 mg; tropisetron andpharmaceutically acceptable salts thereof, in an amount (in tropisetron)of from 5 mg to 15 mg; domperidone and pharmaceutically acceptable saltsand solvates thereof, in an amount (in domperidone) of from 10 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in an amount (in metoclopramide) of from 10 mg to 30 mg;bromopride and pharmaceutically acceptable salts and solvates thereof,in an amount (in bromopride) of from 10 mg to 30 mg; clebopride andpharmaceutically acceptable salts thereof, in an amount (in clebopride)of from 0.5 mg to 1.5 mg; and aprepitant, in an amount of from 40 mg to375 mg.

Preferred Component (b) is a naAEA selected from the group consisting ofalosetron and pharmaceutically acceptable salts and solvates thereof, inan amount (in alosetron) of from 0. 5 mg to 3 mg; granisetron andpharmaceutically acceptable salts and solvates thereof, in particularthe hydrochloride, in an amount (in granisetron) of from 1 mg to 3 mg;ondansetron and pharmaceutically acceptable salts and solvates thereof,in an amount (in ondansetron) of from 4 mg to 24 mg; tropisetron andpharmaceutically acceptable salts thereof, in an amount (in tropisetron)of from 5 mg to 15 mg; domperidone and pharmaceutically acceptable saltsand solvates thereof, in an amount (in domperidone) of from 10 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in an amount (in metoclopramide) of from 10 mg to 30 mg.

A composition comprising (a) a nsPAChA selected from the groupconsisting of propiverine hydrochloride, in an amount of from 15 mg to240 mg, advantageously from 30 mg to 240 mg, preferably from 31 mg to240 mg, most preferably from 31 mg to 180 mg; trospium chloride, in anamount of from 20 mg to 480 mg, advantageously from 40 mg to 480 mg,preferably from 61 mg to 480 mg, most preferably from 61 mg to 360 mg;and glycopyrrolium bromide, in an amount of from 2 mg to 16 mg,advantageously from 4 mg to 16 mg, preferably from 4.1 to 16 mg, mostpreferably from 4.1 mg to 12 mg; and (b) a naAEA selected from the groupconsisting of granisetron hydrochloride in an amount (in granisetron) offrom 1 mg to 3 mg, ondansetron hydrochloride dihydrate in an amount (inondansetron) of from 4 mg to 24 mg, domperidone in an amount of from 10mg to 30 mg; and metoclopramide monohydrochloride monohydrate in anamount (in metoclopramide) of from 10 mg to 30 mg, in admixture with apharmaceutical carrier, is particularly preferred.

The pharmaceutical compositions of the present invention are formulatedin unit form for oral use, preferably in an immediate releaseformulation.

The unit form of the present invention may be a tablet, a capsule, or apre-measured amount of granulate for oral administration comprisingComponent (a) and Component (b). In said unit form the nsPAChA and thenaAEA may be mixed together or separated according to known technologiesin admixture with a pharmaceutical carrier in a pharmaceuticalcomposition.

Component (a) and Component (b) are formulated with conventionalpharmaceutical carriers in known formulations for oral use wherein saidcomponents are mixed together or separated, for example in two tabletsintroduced in a capsule or in a two-compartment capsule or in amultilayer (di-layer) tablet wherein the two components are both in IRform, even though the association nsPAChA/naAEA may be formulated intablets in which one or both of the two components is incontrolled-release formulation, for example as a dispersion of saidcomponent in hydroxypropyl methyl cellulose or in a film-coatedmicrogranule. Advantageously, the nsPAChA, in a ER-formulation is in thecore and the naAEA, in IR-formulation, is in the outer layer inmulti-layer tablets in which, for example, both the core and the outerlayer are coated with a film. Analogously, capsules made of twoseparated parts, one containing Component (a), in IR- or ER-formulationand the other containing Component (b), in IR- or ER-formulation,according to known technologies, may be used.

The pharmaceutical carriers and vehicles are those commonly used for thepreparation of compositions for oral, buccal and parenteral, inparticular transdermal, administration. Appropriate unit forms comprisethe oral forms such as tablets, soft or hard gelatin capsules, powdersor granulates in sachets and suitably measured oral solutions orsuspensions as well as patches for transdermal administration.

Component (a) and Component (b) may also be present in form of one oftheir complexes with a cyclodextrin, for example α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin ormethyl-β-cyclodextrin.

Component (a) and Component (b) may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or additives.

For oral administration, Component (a) and Component (b), together orseparately, are formulated by mixing the active ingredient withconventional pharmaceutical acceptable carriers enabling said activeingredients to be formulated in tablets, dragees, orally disintegratingtablets, capsules and the like.

Carriers for IR tablets include for example starches, cellulose andderivatives thereof; lubricants such as talc, stearic acid or magnesiumstearate; diluents such as talc, powdered cellulose, lactose, starchessuch as maize or corn starch, mannitol, sorbitol; disaggregating agentssuch as microcrystalline cellulose or crospovidone; lubrifiants such aspolyethylenglycol or magnesium stearate; ligands such asmethylcellulose, sodium carboxymethylcellulose, alginic acid, alginates;sweeteners, such as saccharose, dextrose, mannitol, saccharin; orflavoring agents such as natural or synthetic oils.

Carriers for orally disintegrating tablets include for examplelubricants, aggregating, sweetening, flavoring or disaggregating agentsas well as agents improving the buccal mucosa absorption of components(a) and (b) such as sorbitol, mannitol, lactose and cellulose.

The sweeteners contained in the orally disintegrating tablets may benatural, optional reduced sugars such as sucrose, dextrose, xylitol,mannitol or sorbitol, or synthetic product such as sodium saccharine oraspartame.

The flavoring agents are pharmaceutically acceptable flavors and tastesof synthetic and natural oils, the latter extracted from plants, leaves,flowers, fruits and their combinations, such as cinnamon, peppermint,anise and citron leaves, bitter almond, citrus fruits, in particularorange and/or lemon, linden and grapefruit oils. Also chocolate, vanillaor eucalyptus flavor and essences of fruit, in particular apple, pear,peach, strawberry, cherry, apricot, orange, lemon and grapes may beadvantageously used.

The composition according to the present invention may be in form of acapsule containing two tablets as described herein above, one of themcomprising Component (a) and the other comprising Component (b).

Advantageous ER administration formulations are in form of a transdermalpatch manufactured according to known technologies, for administeringthe nsPAChA/antiemetic composition continuously and transdermallythrough a selected area of intact skin in a controlled manner for aprolonged period of time to induce high AChEI blood levels in a humansubject, in particular to a patient suffering from a dementia ofAlzheimer type, said subject or patient being treated with said AChEI.Said high AChEI blood levels enable acetylcholine concentrations in thebrain to rise sufficiently to afford neuroprotection.

Carriers and vehicles for ER formulations include retardant materialssuch as acrylic and methacrylic acid polymers and copolymers; cellulosederivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylethylcellulose, hydroxypropylcelluloses, methylcellulose,ethylcellulose, or sodium carboxymethylcellulose; gums; waxes;glycerides or aliphatic alcohols or a mixture thereof.

In particular, the unit forms of the present invention comprise (a) ansPAChA selected from the group consisting of propiverine hydrochloride,in an amount of from 15 mg to 240 mg, advantageously from 30 mg to 240mg, preferably from 31 mg to 240 mg, most preferably from 31 mg to 180mg; trospium chloride, in an amount of from 20 mg to 480 mg,advantageously from 40 mg to 480 mg, preferably from 61 mg to 480 mg,most preferably from 61 mg to 360 mg; and glycopyrrolium bromide, in anamount of from 2 mg to 16 mg, advantageously from 4 mg to 16 mg,preferably from 4.1 to 16 mg, most preferably from 4.1 mg to 12 mg; and(b) a naAEA selected from the group consisting of domperidone, in anamount of from 10 mg to 30 mg; metoclopramide monohydrochloridemonohydrate, in an amount (in metoclopramide) of from 10 mg to 30 mg;alosetron hydrochloride, in an amount, in alosetron of from 0.5-mg to 3mg), dolasetron mesylate, in an amount of from 50 mg to 300 mg;granisetron hydrochloride in an amount, in granisetron, of from 1 mg to3 mg; ondansetron hydrochloride monohydrate in an amount, inondansetron, of from 4 to 24 mg; tropisetron hydrochloride in an amount,in tropisetron, of from 5 mg to 15 mg; and aprepitant, in an amount offrom 40 mg to 375 mg.

According to an embodiment, the compositions of the present inventionare formulated by mixing a nsPAChA selected from the group consisting ofpropiverine hydrochloride, trospium chloride and glycopyrrolium bromide,as Component (a), and the naAEA, as Component (b), together with apharmaceutical carrier and compressed to a tablet for an immediaterelease or introduced in a soft or hard capsule for an immediaterelease.

An advantageous propiverine/granisetron composition according to thisembodiment comprises

-   -   from 15 mg to 120 mg of propiverine hydrochloride, as Component        (a); and    -   from 1 mg to 3 mg of granisetron (as hydrochloride);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous propiverine/granisetron compositioncomprises

-   -   15 mg of propiverine hydrochloride, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous propiverine/granisetron compositionaccording to this embodiment comprises

-   -   30 mg of propiverine hydrochloride, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous propiverine/granisetron composition according tothis embodiment comprises

-   -   31 mg of propiverine hydrochloride, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous propiverine/granisetron composition according tothis embodiment comprises

-   -   35 mg of propiverine hydrochloride, as Component (a); and    -   2 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous propiverine/granisetron composition according tothis embodiment comprises

-   -   45 mg of propiverine hydrochloride, as Component (a); and    -   2 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A sixth advantageous propiverine/granisetron composition according tothis embodiment comprises

-   -   60 mg of propiverine hydrochloride, as Component (a); and    -   2 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A seventh advantageous propiverine/granisetron composition according tothis embodiment comprises

-   -   60 mg of propiverine hydrochloride, as Component (a); and    -   3 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous propiverine/ondansetron composition according to thisembodiment comprises

-   -   from 15 mg to 120 mg of propiverine hydrochloride, as Component        (a); and    -   from 4 mg to 24 mg of ondansetron (as hydrochloride dihydrate);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous propiverine/ondansetron compositionaccording to this embodiment comprises

-   -   15 mg of propiverine hydrochloride, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous propiverine/ondansetron compositionaccording to this embodiment comprises

-   -   30 mg of propiverine hydrochloride, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous propiverine/ondansetron composition according tothis embodiment comprises

-   -   31 mg of propiverine hydrochloride, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous propiverine/ondansetron composition according tothis embodiment comprises

-   -   45 mg of propiverine hydrochloride, as Component (a); and    -   8 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous propiverine/ondansetron composition according tothis embodiment comprises

-   -   60 mg of propiverine hydrochloride, as Component (a); and    -   8 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous propiverine/tropisetron composition according to thisembodiment comprises

-   -   from 15 mg to 120 mg of propiverine hydrochloride, as Component        (a); and    -   from 5 mg to 15 mg of tropisetron (as hydrochloride), as        Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous propiverine/tropisetron compositionaccording to this embodiment comprises

-   -   35 mg of propiverine hydrochloride, as Component (a); and    -   5 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous propiverine/tropisetron compositionaccording to this embodiment comprises

-   -   35 mg of propiverine hydrochloride, as Component (a); and    -   5 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous propiverine/tropisetron composition according tothis embodiment comprises

-   -   45 mg of propiverine hydrochloride, as Component (a); and    -   10 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous propiverine/dolasetron composition according to thisembodiment comprises

-   -   from 15 mg to 120 mg of propiverine hydrochloride, as Component        (a); and    -   from 50 mg to 300 mg of dolasetron (as mesylate), as Component        (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A particular advantageous propiverine/dolasetron composition accordingto this embodiment comprises

-   -   15 mg, 17.5 mg or 20 mg of propiverine hydrochloride, as        Component (a); and    -   50 mg of dolasetron (as mesylate), as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous propiverine/domperidone composition according to thisembodiment comprises

-   -   from 15 mg to 120 mg of propiverine hydrochloride, as Component        (a); and    -   from 10 mg to 30 mg of domperidone, as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous propiverine/domperidone compositionaccording to this embodiment comprises

-   -   15 mg of propiverine hydrochloride, as Component (a); and    -   10 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous propiverine/domperidone compositionaccording to this embodiment comprises

-   -   31 mg of propiverine hydrochloride, as Component (a); and    -   10 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous propiverine/domperidone composition according tothis embodiment comprises

-   -   45 mg of propiverine hydrochloride, as Component (a); and    -   20 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous propiverine/domperidone composition according tothis embodiment comprises

-   -   60 mg of propiverine hydrochloride, as Component (a); and    -   30 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous propiverine/metoclopramide composition according to thisembodiment comprises

-   -   from 15 mg to 120 mg of propiverine hydrochloride, as Component        (a); and    -   from 10 mg to 30 mg of metoclopramide (as monohydrochloride        monohydrate), as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous propiverine/metoclopramide compositionaccording to this embodiment comprises

-   -   15 mg of propiverine hydrochloride, as Component (a); and    -   10 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous propiverine/metoclopramidecomposition according to this embodiment comprises

-   -   31 mg of propiverine hydrochloride, as Component (a); and    -   10 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous propiverine/metoclopramide composition according tothis embodiment comprises

-   -   45 mg of propiverine hydrochloride, as Component (a); and    -   20 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous propiverine/metoclopramide composition accordingto this embodiment comprises

-   -   60 mg of propiverine hydrochloride, as Component (a); and    -   30 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous trospium/granisetron composition according to thisembodiment comprises

-   -   from 20 mg to 160 mg of trospium chloride, as Component (a); and    -   from 1 mg to 3 mg of granisetron (as hydrochloride);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous trospium/granisetron compositioncomprises

-   -   40 mg of trospium chloride, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        wherein Components (a) and (b) are mixed together and with a        pharmaceutical carrier in an IR formulation.

A second particularly advantageous trospium/granisetron compositionaccording to this embodiment comprises

-   -   60 mg of trospium chloride, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous trospium/granisetron composition according to thisembodiment comprises

-   -   65 mg of trospium chloride, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous trospium/granisetron composition according to thisembodiment comprises

-   -   80 mg of trospium chloride, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous trospium/granisetron composition according to thisembodiment comprises

-   -   80 mg of trospium chloride, as Component (a); and    -   2 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A sixth advantageous trospium/granisetron composition according to thisembodiment comprises

-   -   100 mg of trospium chloride, as Component (a); and    -   2 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A seventh advantageous trospium/granisetron composition according tothis embodiment comprises

-   -   160 mg of trospium chloride, as Component (a); and    -   3 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous trospium/ondansetron composition according to thisembodiment comprises

-   -   from 20 mg to 160 mg of trospium chloride, as Component (a); and    -   from 4 mg to 24 mg of ondansetron (as hydrochloride dihydrate);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous trospium/ondansetron compositionaccording to this embodiment comprises

-   -   40 mg of trospium chloride, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous trospium/ondansetron compositionaccording to this embodiment comprises

-   -   60 mg of trospium chloride, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous trospium/ondansetron composition according to thisembodiment comprises

-   -   80 mg of trospium chloride, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous trospium/ondansetron composition according to thisembodiment comprises

-   -   100 mg of trospium chloride, as Component (a); and    -   8 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous trospium/ondansetron composition according to thisembodiment comprises

-   -   120 mg of trospium chloride, as Component (a); and    -   8 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous trospium/tropisetron composition according to thisembodiment comprises

-   -   from 20 mg to 160 mg of trospium chloride, as Component (a); and    -   from 5 mg to 15 mg of tropisetron (as hydrochloride), as        Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous trospium/tropisetron compositionaccording to this embodiment comprises

-   -   40 mg of trospium chloride, as Component (a); and    -   5 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous trospium/tropisetron compositionaccording to this embodiment comprises

-   -   60 mg of trospium chloride, as Component (a); and    -   5 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous trospium/tropisetron composition according to thisembodiment comprises

-   -   140 mg of trospium chloride, as Component (a); and    -   10 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous trospium/domperidone composition according to thisembodiment comprises

-   -   from 20 mg to 160 mg of trospium chloride, as Component (a); and    -   from 10 mg to 30 mg of domperidone, as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous trospium/domperidone compositionaccording to this embodiment comprises

-   -   40 mg of trospium chloride, as Component (a); and    -   10 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous trospium/domperidone compositionaccording to this embodiment comprises

-   -   70 mg of trospium chloride, as Component (a); and    -   10 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous trospium/domperidone composition according to thisembodiment comprises

-   -   140 mg of trospium chloride, as Component (a); and    -   20 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous trospium/domperidone composition according to thisembodiment comprises

-   -   160 mg of trospium chloride, as Component (a); and    -   30 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous trospium/metoclopramide composition according to thisembodiment comprises

-   -   from 20 mg to 160 mg of trospium chloride, as Component (a); and    -   from 10 mg to 30 mg of metoclopramide (as monohydrochloride        monohydrate), as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous trospium/domperidone compositionaccording to this embodiment comprises

-   -   40 mg of trospium chloride, as Component (a); and    -   10 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous trospium/metoclopramide compositionaccording to this embodiment comprises

-   -   60 mg of trospium chloride, as Component (a); and    -   10 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous trospium/metoclopramide composition according tothis embodiment comprises

-   -   100 mg of trospium chloride, as Component (a); and    -   20 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous trospium/metoclopramide composition according tothis embodiment comprises

-   -   160 mg of trospium chloride, as Component (a); and    -   30 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous glycopyrrolium/granisetron composition according to thisembodiment comprises

-   -   from 2 mg to 16 mg of glycopyrrolium bromide, as Component (a);        and    -   from 1 mg to 3 mg of granisetron (as hydrochloride);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous glycopyrronium/granisetron compositioncomprises

-   -   2 mg of glycopyrrolium bromide, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous glycopyrrolium/granisetroncomposition according to this embodiment comprises

-   -   2.5 mg of glycopyrrolium bromide, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous glycopyrrolium/granisetron composition according tothis embodiment comprises

-   -   3 mg of glycopyrrolium bromide, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous glycopyrrolium/granisetron composition accordingto this embodiment comprises

-   -   5 mg of glycopyrrolium bromide, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous glycopyrrolium/granisetron composition according tothis embodiment comprises

-   -   10 mg of glycopyrrolium bromide, as Component (a); and    -   2 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A sixth advantageous glycopyrrolium/granisetron composition according tothis embodiment comprises

-   -   12 mg of glycopyrrolium bromide, as Component (a); and    -   2 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A seventh advantageous glycopyrrolium/granisetron composition accordingto this embodiment comprises

-   -   16 mg of glycopyrrolium bromide, as Component (a); and    -   3 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous glycopyrrolium/ondansetron composition according to thisembodiment comprises

-   -   from 2 mg to 16 mg of glycopyrrolium bromide, as Component (a);        and    -   from 4 mg to 24 mg of ondansetron (as hydrochloride dihydrate);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous glycopyrrolium/ondansetron compositionaccording to this embodiment comprises

-   -   2 mg of glycopyrrolium bromide, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous glycopyrrolium/ondansetroncomposition according to this embodiment comprises

-   -   3 mg of glycopyrrolium bromide, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous glycopyrrolium/ondansetron composition according tothis embodiment comprises

-   -   4 mg of glycopyrrolium bromide, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous glycopyrrolium/ondansetron composition accordingto this embodiment comprises

-   -   8 mg of glycopyrrolium bromide, as Component (a); and    -   8 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous glycopyrrolium/ondansetron composition according tothis embodiment comprises

-   -   10 mg of glycopyrrolium bromide, as Component (a); and    -   12 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A sixth advantageous glycopyrrolium/ondansetron composition according tothis embodiment comprises

-   -   12 mg of glycopyrrolium bromide, as Component (a); and    -   16 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A seventh advantageous glycopyrrolium/ondansetron composition accordingto this embodiment comprises

-   -   16 mg of glycopyrrolium bromide, as Component (a); and    -   20 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous glycopyrrolium/tropisetron composition according to thisembodiment comprises

-   -   from 2 mg to 16 mg of glycopyrrolium bromide, as Component (a);        and    -   from 5 mg to 15 mg of tropisetron (as hydrochloride), as        Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous glycopyrrolium/tropisetron compositionaccording to this embodiment comprises

-   -   2.5 mg of glycopyrrolium bromide, as Component (a); and    -   5 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous glycopyrrolium/tropisetroncomposition according to this embodiment comprises

-   -   4 mg of glycopyrrolium bromide, as Component (a); and    -   5 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous glycopyrrolium/tropisetron composition according tothis embodiment comprises

-   -   10 mg of glycopyrrolium bromide, as Component (a); and    -   10 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous glycopyrrolium/alosetron composition according to thisembodiment comprises

-   -   from 2.1 mg to 16 mg of glycopyrrolium bromide, as Component        (a); and    -   from 0.5 mg to 3 mg of alosetron (as hydrochloride), as        Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A particular advantageous glycopyrrolium/alosetron composition accordingto this embodiment comprises

-   -   2.5 mg of glycopyrrolium bromide, as Component (a); and    -   2 mg of alosetron (as hydrochloride), as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous glycopyrrolium/domperidone composition according to thisembodiment comprises

-   -   from 4 mg to 16 mg of glycopyrrolium bromide, as Component (a);        and    -   from 10 mg to 30 mg of domperidone, as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous glycopyrrolium/domperidone compositionaccording to this embodiment comprises

-   -   4 mg of glycopyrrolium bromide, as Component (a); and    -   10 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous glycopyrrolium/domperidonecomposition according to this embodiment comprises

-   -   8 mg of glycopyrrolium bromide, as Component (a); and    -   10 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous glycopyrrolium/domperidone composition according tothis embodiment comprises

-   -   8 mg of glycopyrrolium bromide, as Component (a); and    -   20 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous glycopyrrolium/domperidone composition accordingto this embodiment comprises

-   -   10 mg of glycopyrrolium bromide, as Component (a); and    -   30 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous glycopyrrolium/metoclopramide composition according tothis embodiment comprises

-   -   from 4 mg to 16 mg of glycopyrrolium bromide, as Component (a);        and    -   from 10 mg to 30 mg of metoclopramide (as monohydrochloride        monohydrate), as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous glycopyrrolium/metoclopramidecomposition according to this embodiment comprises

-   -   4 mg of glycopyrrolium bromide, as Component (a); and    -   10 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous glycopyrrolium/metoclopramidecomposition according to this embodiment comprises

-   -   8 mg of glycopyrrolium bromide, as Component (a); and    -   10 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous glycopyrrolium/metoclopramide composition accordingto this embodiment comprises

-   -   8 mg of glycopyrrolium bromide, as Component (a); and    -   20 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous glycopyrrolium/metoclopramide compositionaccording to this embodiment comprises

-   -   10 mg of glycopyrrolium bromide, as Component (a); and    -   30 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

According to a second embodiment, the compositions of the presentinvention are formulated by mixing a nsPAChA selected from the groupconsisting of propiverine hydrochloride, trospium chloride andglycopyrrolium bromide, as the Component (a) with a pharmaceuticalcarrier for an immediate or extended release in tablets (Tablet A) andthe naAEA Component (b), separately, with a pharmaceutical carrier foran immediate or extended release in tablets (Tablet B) and introducingTablet A and Tablet B in a capsule for oral administration as describedfor example in GB 1204580 or in US 2007/0224259, thus obtaining a unitform to be administered to a patient suffering from a dementia ofAlzheimer type.

An advantageous propiverine/granisetron unit form according to thisembodiment consists of preferably hard gelatin capsules each containing

-   -   Tablet A comprising from 15 mg to 120 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation; and    -   Tablet B, comprising from 1 to 3 mg of granisetron (as        hydrochloride), as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A first particularly advantageous propiverine/granisetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 15 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, comprising 1 mg of granisetron (as hydrochloride), as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A second particularly advantageous propiverine/granisetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 30 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, comprising 2 mg of granisetron (as hydrochloride), as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A third advantageous propiverine/granisetron unit form according to thisembodiment contains

-   -   Tablet A comprising 45 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, comprising 3 mg of granisetron (as hydrochloride), as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

An advantageous propiverine/ondansetron unit form according to thisembodiment consists of preferably hard gelatin capsules each containing

-   -   Tablet A comprising from 15 mg to 120 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation; and    -   Tablet B, comprising from 4 to 24 mg of ondansetron (as        hydrochloride dihydrate), as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A first particularly advantageous propiverine/ondansetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 15 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, comprising 4 mg of ondansetron (as hydrochloride        dihydrate), as Component (b), in admixture with a pharmaceutical        carrier in an IR-formulation.

A second particularly advantageous propiverine/ondansetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 30 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, comprising 8 mg of ondansetron (as hydrochloride        dihydrate), as Component (b), in admixture with a pharmaceutical        carrier in an IR-formulation.

A third advantageous propiverine/ondansetron unit form according to thisembodiment contains

-   -   Tablet A comprising 45 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, comprising 8 mg of ondansetron (as hydrochloride        dihydrate), as Component (b), in admixture with a pharmaceutical        carrier in an IR-formulation.

An advantageous propiverine/tropisetron unit form according to thisembodiment consists of preferably hard gelatin capsules each containing

-   -   Tablet A comprising from 15 mg to 120 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation; and    -   Tablet B, comprising from 5 to 15 mg of tropisetron as Component        (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A first particularly advantageous propiverine/tropisetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 15 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in an        IR formulation; and    -   Tablet B, comprising 5 mg of tropisetron (as hydrochloride), as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A second particularly advantageous propiverine/tropisetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 31 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, comprising 5 mg of tropisetron (as hydrochloride), as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

An advantageous propiverine/domperidone unit form according to thisembodiment consists of preferably hard gelatin capsules each containing

-   -   Tablet A comprising from 15 mg to 120 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation; and    -   Tablet B, comprising from 10 to 30 mg of domperidone as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A particularly advantageous propiverine/domperidone unit form accordingto this embodiment contains

-   -   Tablet A comprising 31 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, comprising 10 mg of domperidone as Component (b), in        admixture with a pharmaceutical carrier in an IR-formulation.

An advantageous propiverine/metoclopramide unit form according to thisembodiment consists of preferably hard gelatin capsules each containing

-   -   Tablet A comprising from 15 mg to 120 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation; and    -   Tablet B, comprising from 10 to 30 mg of metoclopramide (as        monohydrochloride monohydrate) as Component (b), in admixture        with a pharmaceutical carrier in an IR-formulation.

A particularly advantageous propiverine/metoclopramide unit formaccording to this embodiment contains

-   -   Tablet A comprising 20 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, comprising 15 mg of metoclopramide (as        monohydrochloride monohydrate) as Component (b), in admixture        with a pharmaceutical carrier in an IR-formulation.

According to a third embodiment, the compositions according to thepresent invention are formulated in a di-layer tablet, one comprising ansPAChA selected from the group consisting of propiverine hydrochloride,trospium chloride and glycopyrrolium bromide and the other comprising anaAEA, which releases the two drug doses, in which the release of a drugfrom one drug-containing layer does not interfere with the release of adrug from the other drug-containing layer as described for example in WO2006/089493.

An advantageous propiverine/granisetron composition according to thisembodiment consists of

-   -   Layer A, comprising from 15 mg to 120 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation and    -   Layer B, comprising from 1 to 3 mg of granisetron, as        hydrochloride, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A first particularly advantageous propiverine/granisetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 25 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation and    -   Layer B, comprising 1 mg of granisetron, as hydrochloride, as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A second particularly advantageous propiverine/granisetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 31 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation and    -   Layer B, comprising 2 mg of granisetron, as hydrochloride, as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A third particularly advantageous propiverine/granisetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 40 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation and    -   Layer B, comprising 2 mg of granisetron, as hydrochloride, as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

An advantageous propiverine/ondansetron composition according to thisembodiment consists of

-   -   Layer A, comprising from 15 mg to 120 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation and    -   Layer B, comprising from 4 to 24 mg of ondansetron, as        hydrochloride dihydrate, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A first particularly advantageous propiverine/ondansetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 15 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation and    -   Layer B, comprising 4 mg of ondansetron, as hydrochloride        dihydrate, as Component (b), in admixture with a pharmaceutical        carrier in an IR-formulation.

A second particularly advantageous propiverine/ondansetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 50 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation and    -   Layer B, comprising 8 mg of ondansetron, as hydrochloride        dihydrate, as Component (b), in admixture with a pharmaceutical        carrier in an IR-formulation.

An advantageous propiverine/tropisetron composition according to thisembodiment consists of

-   -   Layer A, comprising from 15 mg to 120 mg propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation and    -   Layer B, comprising from 5 to 15 mg of tropisetron, as        hydrochloride, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A particularly advantageous propiverine/tropisetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 31 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation and    -   Layer B, comprising 5 mg of tropisetron, as hydrochloride, as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

An advantageous propiverine/domperidone composition according to thisembodiment consists of

-   -   Layer A, comprising from 15 mg to 120 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation and    -   Layer B, comprising from 10 to 30 mg of domperidone, as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A particularly advantageous propiverine/domperidone compositionaccording to this embodiment consists of

-   -   Layer A, comprising 31 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation and    -   Layer B, comprising 10 mg of domperidone, as Component (b), in        admixture with a pharmaceutical carrier in an IR-formulation.

An advantageous propiverine/metoclopramide composition according to thisembodiment consists of

-   -   Layer A, comprising from 15 mg to 120 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation and    -   Layer B, comprising from 10 to 30 mg of metoclopramide, as        monohydrochloride hydrate, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A particularly advantageous propiverine/metoclopramide compositionaccording to this embodiment consist of

-   -   Layer A, comprising 31 mg of propiverine hydrochloride, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation and    -   Layer B, comprising 10 mg of metoclopramide (as        monohydrochloride monohydrate) as Component (b), in admixture        with a pharmaceutical carrier in an IR-formulation.

The above combined pharmaceutical compositions are able to assuregreater and longer efficacy and less adverse effects of co-administeredAChEIs by allowing the safe and tolerable administration of larger andthus more therapeutically effective quantities (from 2.5 to 7 times themaximum recommended doses) of said AChEIs in human subjects treated withsaid AChEI. In particular, by inducing very high blood levels in humansubjects, the above combined compositions assure an increasedconcentration of AChEIs to the CNS of patients suffering from a dementiaof Alzheimer type which are treated even with very high doses of AChEI.

The pathologic conditions treated with the composition of the presentinvention include, but are not limited to, Alzheimer's disease,Parkinson's disease dementia, and other chronic disorders of humancognitive and neurobehavioral function that are treated, in part, bypharmaceuticals intended to augment brain acetylcholine-mediatedneurotransmission. The composition of the present invention can also beused to treat acute cognitive disorders such as post-surgical delirium.

The therapeutic efficacy is measured by the degree to which cognitiveand other neurobehavioral disabilities associated with dementias of theAlzheimer type, as documented by the use of standard scales, arereduced.

Thus, the present invention also provides a method for inducingneuroprotection, thus combating neurodegeneration, and consequentlyslowing disease progression in a patient suffering from a dementia ofthe Alzheimer type, which comprises administering to said patient anAChEI daily dose which is at least 2.5, up to 7 times the maximumrecommended daily dose of said AChEI used in the treatment of Alzheimertype dementias, in combination with a pharmaceutical compositioncomprising an nsPAChA selected from the group consisting of propiverinehydrochloride, in an amount of from 15 mg to 240 mg, advantageously from30 mg to 240 mg, preferably from 31 mg to 240 mg; trospium chloride, inan amount of from 20 mg to 480 mg, advantageously from 40 mg to 480 mg,preferably from 61 mg to 480 mg; and glycopyrrolium bromide, in anamount of from 2 mg to 16 mg, advantageously from 4 mg to 16 mg,preferably from 4.1 to 16 mg; and (b) a non-anticholinergic antiemeticagent (naAEA); in admixture with a pharmaceutical carrier. Saidpharmaceutical composition is exhaustively illustrated herein above.

II. Second Aspect of the Present Invention.

In a second aspect, the present invention provides an improved method toaugment and extend the efficacy of current cholinergic therapies forAlzheimer type dementias by mitigating the common dose-limiting adverseevents of cholinomimetic treatments of said Alzheimer type dementiasthat arise as a result of the concomitant excessive stimulation ofcholinergic receptors in the PNS. Drugs that act to selectively inhibitthe activation of all or nearly all the muscarinic receptors in the PNS,but not in the CNS, resulting from cholinomimetic therapy have thepotential to reduce the adverse effects, such that higher cholinomimeticdoses can be administered leading to greater and more prolongedantidementia efficacy with fewer peripherally mediated side effects. Bycombining an extended release cholinomimetic with a peripheralanticholinergic having an advantageous duration of pharmacologic action,in a single dosage form, the benefits to patients of an even longerduration of action is also achieved.

In particular, the invention provides a method for inducingneuroprotection in a patient suffering from an Alzheimer type dementia,which comprises administering said patient an AChEI dose which is atleast 2.5, up to 7 times the dose used in the treatment of Alzheimertype dementias, in combination with a nsPAChA dose which is more thantwice, up to 8 times the dose used in the anticholinergic therapy.

More particularly, the invention provides a method for inducingneuroprotection in a patient suffering from an Alzheimer type dementia,which comprises administering to said patient a nsPAChA selected fromthe group consisting of solifenacin, pharmaceutically acceptable saltsand compounds of solifenacin, pharmaceutically acceptable salts oftrospium, pharmaceutically acceptable salts of glycopyrrolium,propiverine and pharmaceutically acceptable salts of propiverine, saidnsPAChA being administered at a dose which is more than twice to eighttimes, preferably from 2.5 to 8 times the dose used for theanticholinergic therapy, in combination with a dose of said AChEI whichis from 2.5 to 7 times the dose used for the treatment of Alzheimer typedementia. The pharmaceutically acceptable salts of propiverine andsolifenacin include the propiverine and solifenacin quaternary salts, inparticular the methyl chloride, the methyl iodide and the methyl bromidethereof.

This finding is surprising because an increase in the blood levels of adrug normally also increases the risk of side effects while, in the caseof the combined nsPAChA/AChEI treatment according to the presentinvention, the most common and dangerous adverse effects are suppressed.

The present invention also provides a pharmaceutical compositioncomprising, as an active ingredient, an nsPAChA selected from the groupconsisting of solifenacin and pharmaceutically acceptable salts thereof,propiverine and pharmaceutically acceptable salts thereof, and trospiumpharmaceutically acceptable salts, in an amount which is from more than200% to 800% the maximum amount of said nsPAChA contained incompositions indicated for the anticholinergic therapy. This compositionis useful for inducing neuroprotection and combating neurodegenerationin a patient suffering from Alzheimer type dementia, who is treated withan AChEI dose which is from 250% to 700% the maximum recommended dose ofsaid AChEI.

A. The nsPAChAs

Advantageously, the used nsPAChAs are quaternary ammonium nsPAChAs,sulfonium nsPAChAs, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-iso-quinolinecarboxylate (solifenacin) andits pharmaceutically acceptable salts, (1-methylpiperidin-4-yl)2,2-di(phenyl)-2-propoxyacetate (propiverine) and its pharmaceuticallyacceptable salts, 1,4,5,6-tetrahydro-1-methylpyrimidin-2-ylmethylα-cyclohexyl-α-hydroxy-α-phenylacetate (oxyphencyclimine) and itspharmaceutically acceptable salts,(R)—N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine(tolterodine) and its pharmaceutically acceptable salts. Said nsPAChAs,preferably, are compounds with duration of action of at least 6 hours,advantageously from 8 to 24 hours, more advantageously from 10 to 24hours, preferably from 12 to 24 hours, even though nsPAChAs having anappropriate duration of action corresponding to the duration of actionof the concomitantly administered AChEI may be successfully used.

Particularly advantageous quaternary ammonium nsPAChAs or sulfoniumnsPAChAs are compounds of formula II

wherein

-   -   R is a radical selected from the group consisting of those of        formulas (a)-(e)

-   -   -   A being methyl and A′ being (C₁-C₄)alkyl or 2-fluoroethyl            group or A and A′ forming a 1,4-butylene or 1,5-pentylene            chain, L being hydrogen or methoxy, Alk and Alk′ each being            (C₁-C₄)alkyl and Y being a bivalent radical selected from            the group consisting of 1,2-ethylene, 1,3-propylene,            1,4-butylene and 2-oxa-1,3-propylene; the corresponding            counter ion being a pharmaceutically acceptable anion, such            as a chloro, bromo, iodo, tartrate, hydrogen tartrate,            succinate, maleate, fumarate, sulfate, hydrogen sulfate or            methylsulfate anion;

    -   n and m, independently, are zero or 1;

    -   X is a (C₂-C₃)alkylene group;

    -   R₁ and R₂ are each phenyl, cyclopentyl, cyclohexyl,        1-cyclohexenyl, 2-thienyl and, when R is a radical (a), also        each represents (C₁-C₄)alkyl;

    -   R₃ is H or OH or, only when R is a radical (a), also a COOAlk        group, Alk being a (C₁-C₄)alkyl group.

Exemplary nsPAChAs of formula II above used for preparing medicamentsfor the treatment of Alzheimer type dementia in combination with AchEIsare

-   -   anisotropine methylbromide [R=(a), A=A′=CH₃, L=H; n=1; m=0;        R₁═R₂=n-C₃H₇; R₃═H;];    -   ciclotropium bromide [R=(a), A=CH₃, A′=isopropyl, L=H; n=1; m=0;        R₁=phenyl; R₂=cyclopentyl; R₃═H];    -   flutropium bromide [R=(a), A=CH₃, A′=2-fluoroethyl, L=H; n=1;        m=0; R₁═R₂=phenyl; R₃═OH];    -   homatropine methylbromide [R=(a), A=A′=CH₃, L=H; n=1; m=0;        R₁=phenyl; R₂═R₃═H];    -   sintropium bromide; [R=(a), A=CH₃, A′=isopropyl, L=H; n=1; m=0;        R₁═R₂=n-C₃H₇; R₃═H];    -   tematropium metilsulfate [R=(a), A=A′=CH₃, L=H; n=1; m=0;        R₁=phenyl; R₂═COOC₂H₅; R₃═H];    -   tropenziline bromide [R=(a), A=A′=CH₃, L=methoxy; n=1; m=0;        R₁═R₂=phenyl, R₃═OH];    -   trospium chloride [R=(a), A+A′=1,4-butylene, L=H; n=1; m=0;        R₁═R₂=phenyl; R₃═OH];    -   clidinium bromide [R=(b)-3-, Alk=methyl; n=1; m=0; R₁═R₂=phenyl;        R₃═OH];    -   droclidinium bromide [R=(b)-3-, Alk=methyl; n=1; m=0; R₁=phenyl;        R₂=cyclopentyl; R₃═OH];    -   benzilonium bromide [R=(c)-3-, both Alk and Alk′=ethyl; n=1;        m=0; R₁═R₂=phenyl; R₃═OH];    -   benzopyrronium bromide [R=(c)-3-, both Alk and Alk′=methyl; n=1;        m=0; R₁═R₂=phenyl; R₃═OH];    -   cyclopyrronium bromide [R=(c)-3-, Alk=methyl and Alk′=ethyl;        n=1; m=0; R₁=phenyl; R₂=cyclopentyl; R₃═H];    -   glycopyrronium bromide (glycopyrrolate) [R=(c)-3-, both Alk and        Alk′=methyl; n=1; m=0; R₁=phenyl; R₂=cyclopentyl; R₃═H];    -   heteronium bromide [R=(c)-3-, both Alk and Alk′=methyl n=1; m=0;        R₁=phenyl; R₂=2-thienyl; R₃═OH];    -   hexopyrronium bromide [R=(c)-3-, both Alk and Alk′=methyl; n=1;        m=0; R₁=phenyl; R₂=cyclohexyl; R₃═H];    -   oxypyrronium bromide [R=(c)-2-, both Alk and Alk′=methyl; n=1;        m=1; X=1,2-ethylene; R₁=phenyl; R₂=cyclohexyl; R₃═OH];    -   ritropirronium bromide [R=(c)-3-, both Alk and Alk′=methyl; n=1;        m=0; R₁=phenyl; R₂=cyclopentyl; R₃═OH];    -   etipirium iodide [R=(d), Alk=methyl, Y=1,2-ethylene; n=1; m=1;        X=1,2-ethylene; R₁═R₂=phenyl; R₃═OH];    -   fenclexonium methylsulfate [R=(d), Alk=CH₃, Y=1,3-propylene;        n=0; m=1; X=1,2-ethylene; R₁=phenyl; R₂=1-cyclohexenyl; R₃═H];    -   tricyclamol chloride (procyclidine methochloride) [R=(d),        Alk=methyl, Y=1,2-ethylene; n=0; m=1; X=1,2-ethylene; R₁=phenyl;        R₂=cyclohexyl; R₃═OH];    -   tiemonium iodide [R=(d), Alk=methyl, Y=2-oxa-1,3-propylene; n=0;        m=1; X=1,2-ethylene; R₁=phenyl; R₂=2-thienyl; R₃═OH];    -   hexasonium iodide [R=(e); n=1; m=1; X=1,2-ethylene; R₁=phenyl;        R₂=cyclohexyl; R₃═H]; and    -   oxysonium iodide [R=(e); n=1; m=1; X=1,2-ethylene; R₁=phenyl;        R₂=cyclohexyl; R₃═OH.

A nsPAChA selected from the group consisting of(1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (solifenacin) or apharmaceutically acceptable salt or compound thereof,1-methyl-4-[(2,2-diphenyl-2-n-propoxy)acetoxy]piperidine (propiverine)and pharmaceutically acceptable salts thereof,3-(2-hydroxy-2,2-diphenylacetoxy)-spiro[bicyclo[3.2.1]octane-8,1′-pyrrolidin]-1′-ium(trospium) pharmaceutically acceptable salts, and3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium(glycopyrrolium) pharmaceutically acceptable salts, are particularlyadvantageous.

Solifenacin and pharmaceutically acceptable salts and compounds thereof,including the quaternary ammonium salts thereof, and their preparationare described in U.S. Pat. No. 6,017,927. Methods for the preparationand for the purification of solifenacin and its salts, in particular ofsolifenacin succinate, are described for example in WO 2007/076116, WO2009/139002, WO 2011/003624 and WO 2012/001481.

Propiverine and pharmaceutically acceptable salts thereof, in particularits hydrochloride, are described in DD 106643, CN 1285348, CN102218063(A), KR 2005-0011138, KR 2005-0011139, KR20110111782 (A) and inWO 2011/114195. The propiverine quaternary salts, i.e. the (C1-C4)alkylpropiverinium halides may be prepared by reacting1-methyl-4-[(2,2-diphenyl-2-propoxy)acetoxy]piperidine (propiverinebase) with a (C1-C4)alkyl halide (chloride, bromide or iodide), thepropiverine base starting material being also obtained as crude productas described in WO 2011/114195 or by hydrolysis of propiverinehydrochloride, which is an easily available commercial product alsoobtainable for example as described in DD 106643, CN 1285348, CN102218063(A) KR 2005-0011138, KR 2005-0011139, KR20110111782 (A) or inthe aforesaid WO 2011/114195. In practice, an aqueous suspension ofpropiverine hydrochloride is treated with an inorganic base and crudepropiverine base is recovered by extraction from an organic solvent andevaporation of the solvent; and the residue is treated with a(C1-C4)alkyl (preferably methyl) halide (chloride, bromide or iodide) inan alcoholic solution and the1-alkyl-1-methyl-4-[(2,2-diphenyl-2-propoxy)acetoxy]piperidinium halidewhich precipitates is isolated.

Trospium pharmaceutically acceptable salts, in particular its chloride,may be prepared as described in U.S. Pat. No. 3,480,626 and othertrospium pharmaceutically acceptable salts, in particular the tartrate,maleate, fumarate and succinate salts thereof, are cited in US2006/0293356.

Glycopyrronium pharmaceutical acceptable salts, in particular thebromide, are obtainable according to U.S. Pat. No. 2,956,062.

Trospium is a long-acting nsPAChA whose absorbed amount has an averageplasma half-life of about 18 hours. Solifenacin succinate is anothernsPAChA having long-acting characteristics; the elimination half-life ofsolifenacin after chronic dosing is approximately 45 to 68 hours(VESICare® Tablets label).

Also other quaternary ammonium salts or sulfonium salts of formula IIabove, such as homatropine quaternary salts, anisotropine quaternarysalts, clidinium quaternary salts, benzilonium quaternary salts aresuitable nsPAChAs, but their half-life is short.

According to the present invention, in order to assure neuroprotectionthe nsPAChAs are concurrently or sequentially administered with theabove AChEIs, at a daily dose which is from more than 200% to 800% therecommended dose of said nsPAChA used in the anticholinergic therapy.

According to a preferred embodiment, trospium chloride, at daily dosesof from more than 80 mg to 320 mg in an IR formulation or from more than120 mg to 480 mg in an ER formulation; solifenacin succinate, at dailydoses of from more than 20 mg to 80 mg in an IR formulation; propiverinehydrochloride, at daily doses of from more than 60 mg to 120 mg in an IRor ER formulation; and glycopyrrolium, at daily doses of from 8.2 mg to64 mg, in IR or ER formulation, allow the administration of AChEI dosesthat are from 2.5 to 7 times higher than their maximum recommended dailydoses, in order to induce AChEI blood levels, not attainable withhypothetical identical doses of AChEI, administered alone or incombination with lower doses of nsPAChA.

In particular, the aforementioned daily doses of trospium chloride,solifenacin succinate, propiverine hydrochloride or glycopyrroliumbromide allow the safe administration of donepezil hydrochloride at adaily dose of from 25 mg to 151 mg; of rivastigmine hydrogen tartrate,at a daily dose of from 30 mg to 93 mg; galantamine hydrobromide, at adaily dose of from 60 mg to 224 mg; and huperzine A, at a dose up to 4.8mg, without inducing the most dangerous adverse effects of said AChEI.

For the intended use, the nsPAChA is formulated in pharmaceuticalcompositions comprising, as an active ingredient thereof, said nsPAChAin admixture with a pharmaceutical carrier.

In brand or generic nsPAChAs used in the anticholinergic therapy, forexample, anisotropine hydrobromide is available in unit forms at themaximum dose of 50 mg; butylscopolamine bromide is available in unitforms at the maximum dose of 20 mg; cimetropium bromide is available inunit forms at the maximum dose of 50 mg; clidinium bromide, is availablein unit forms, also comprising 2.5 mg chlordiazepoxide, at the maximumdose of 5 mg; glycopyrrolium bromide is available in unit forms at themaximum dose of 2 mg; otilonium bromide is available in unit forms atthe maximum dose of 40 mg; prifinium bromide is available in unit formsat the maximum dose of 60 mg; propiverine hydrochloride is available inIR unit forms at the maximum dose of 15 mg and in a ER unit form at themaximum dose of 30 mg; solifenacin succinate is available in unit formsat the maximum dose of 10 mg; timepidium bromide is available in unitforms at the maximum dose of 30 mg; trospium chloride is available in IRunit forms at the maximum dose of 20 mg and in ER unit form at themaximum dose of 60 mg; and valethamate bromide is available in unitforms, also comprising 325 mg paracetamol, at the maximum dose of 10 mg.

The pharmaceutical compositions of the present invention for use forinducing neuroprotection and combating neurodegeneration, as illustratedabove, contain an nsPAChA, for example selected from the groupconsisting of those mentioned in the preceding paragraph, at a dose offrom more than 200% to 800%, advantageously from 210% to 800%,preferably from 250% to 800%, the maximum dose defined in saidparagraph, in admixture with a pharmaceutical carrier.

For example, said pharmaceutical compositions comprise an nsPAChAselected from the group consisting of anisotropine hydrobromide, in anamount of from more than 100 mg to 400 mg, preferably from 110 mg to 400mg; butylscopolamine bromide, in an amount of from more than 40 mg to160 mg, preferably from 44 mg to 160 mg; cimetropium bromide, in anamount of from more than 100 mg to 400 mg, preferably from 110 mg to 400mg; clidinium bromide, in an amount of from more than 10 mg to 40 mg,preferably from 11 mg to 40 mg; glycopyrrolium bromide, in an amount offrom more than 4 mg to 16 mg, preferably from 4.2 mg to 16 mg; otiloniumbromide, in an amount of from more than 80 mg to 320 mg, preferably from84 mg to 320 mg; prifinium bromide, in an amount of from more than 60 mgto 240 mg, preferably from 63 mg to 240 mg; propiverine hydrochloride,in an amount of from more than 30 mg to 240 mg, preferably from 31.5 mgto 240 mg; solifenacin succinate, in an amount of from more than 20 mgto 80 mg, preferably from 21 mg to 80 mg; timepidium bromide, in anamount of from more than 60 mg to 240 mg, preferably from 63 mg to 240mg; trospium chloride, in an amount of from more than 40 mg to 480 mg,preferably from 42 mg to 480 mg; and valethamate bromide, in an amountof from more than 20 mg to 80 mg, preferably from 21 mg to 80 mg; inadmixture with a pharmaceutical carrier.

According to a preferred embodiment, the present invention provides apharmaceutical composition comprising, as an active ingredient, annsPAChA selected from the group consisting of glycopyrrolium bromide, inan amount of from 4.1 mg to 16 mg, preferably from 4.1 mg to 12 mg, inan IR formulation; glycopyrrolium bromide, in an amount of from 8 to 64mg, preferably from 16 mg to 64 mg, in an ER formulation trospiumchloride in an amount of from 42 mg to 160 mg, preferably from 60 mg to160 mg, in admixture with a pharmaceutical carrier in an IR formulation;trospium chloride in an amount of from 126 mg to 480 mg, preferably from160 mg to 480 mg, in admixture with a pharmaceutical carrier in an ERformulation; solifenacin succinate in an amount of from 21 mg to 80 mg,preferably from 25 mg to 80 mg, in admixture with a pharmaceuticalcarrier in an IR formulation; propiverine hydrochloride in an amount offrom 31.5 mg to 120 mg, preferably from 35 mg to 120 mg, in admixturewith a pharmaceutical carrier in an IR formulation; and propiverinehydrochloride in an amount of from 61.5 mg to 240 mg, preferably from 65mg to 240 mg, in admixture with a pharmaceutical carrier in an ERformulation.

The aforementioned combination of the synergistic action of the nsPAChAs(peripheral only) and of the AChEI (both central and peripheral),inducing a theoretically infinite increase of the nsPAChA/AChEI pairdoses without untoward peripheral anticholinergic side effects, allowsthe treatment of patients suffering from dementia of Alzheimer type withoverdoses of both nsPAChA and AChEI and combats neurodegeneration. Thus,these pharmaceutical compositions are useful for inducingneuroprotection and combating neurodegeneration in a patient, sufferingfrom an Alzheimer type dementia, who is treated with a dose an AChEIwhich is from 2.5 to 7 times the maximum recommended dose of said AChEI.

Thus, for example, the above pharmaceutical compositions containing annsPAChA, may be used in combination with donepezil or a pharmaceuticallyacceptable salt thereof, in particular donepezil hydrochloride at a doseof from 25 mg to 151 mg; rivastigmine or a pharmaceutically acceptablesalt thereof, in particular rivastigmine hydrogen tartrate, at a dose inrivastigmine of from 30 mg to 93 mg; and galantamine or apharmaceutically acceptable salt thereof, in particular galantaminehydrobromide, at a dose in galantamine of from 60 mg to 224 mg, forinducing neuroprotection and combating neurodegeneration.

According to an advantageous embodiment, the pharmaceuticalcompositions, prepared by using the nsPAChAs according to the presentinvention, are present in unit forms also containing other activeingredients, in particular an AChEI at the aforementioned overdoses, toassure neuroprotection and to combat neurodegeneration in a patientsuffering from a dementia of Alzheimer type.

B. The AChEIs

Advantageous AChEIs are those currently used or tested for thisindication, such as 1,2,3,4-tetrahydro-9-acridinamine (tacrine),9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline (ipidacrine);(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one(donepezil) and its pharmaceutically acceptable salts, in particular thehydrochloride,3-[2-(1-benzyl-4-piperidyl)ethyl]-5,7,-dihydro-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one(icopezil) and its pharmaceutically acceptable salts, in particular themaleate,3-[1-benzylpiperdin-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)propan-1-one(zanapezil) and its pharmaceutically acceptable salts, in particular thefumarate, (S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenylcarbamate (rivastigmine) and its pharmaceutically acceptable salts, inparticular the hydrogen (2R,3R)-tartrate,4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol(galantamine) and its pharmaceutically acceptable salts, in particularthe hydrobromide;(1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0^(2,7)]trideca-2(7),3,10-trien-5-one(huperzine A) and phenserine and its analogs encompassed by the generalformula I

wherein Q is a phenyl group optionally substituted with a (C₁-C₄)alkylor with a methoxy group, Z is an oxygen or sulfur atom or a N-E′radical, E and E′, independently, are hydrogen or a methyl groupoptionally substituted with a phenyl or benzyl group; andpharmaceutically acceptable salts thereof.

Exemplary AChEIs of formula (I), described in U.S. Pat. No. 6,683,105,are phenserine (Q=phenyl; E=CH₃; Z═N—CH₃); (−)-N¹,N⁸-bisnorphenserine(Q=phenyl; E=H; Z═N—H); 4′-methoxyphenserine (Q=4′-methoxyphenyl; E=CH₃;Z═N—CH₃); (−)-N¹,N⁸-bisbenzylnorphenserine (Q=phenyl; E=CH₂C₆H₅;Z═N—CH₂C₆H₅); tolserine (Q=o-tolyl; E=CH₃; Z═N—CH₃);N¹-benzylnortolserine (Q=o-tolyl; E=CH₃; Z═N—CH₂—C₆H₅);N¹-phenethylnortolserine (Q=o-tolyl; E=CH₃; Z═N—CH₂—CH₂—C₆H₅);N¹-nortolserine (Q=o-tolyl; E=CH₃; Z═N—H); N⁸-benzylnortolserine(Q=o-tolyl; E=N—CH₂—C₆H₅; Z═N—CH₃); N⁸-phenethylnortolserine (Q=o-tolyl;E=N—CH₂—CH₂—C₆H₅; Z═N—CH₃); N⁸-nortolserine (Q=o-tolyl; E=H; Z═N—CH₃);N¹,N⁸-bisnortolserine (Q=o-tolyl; E=H; Z═N—H);(−)-N¹,N⁸-bisbenzylnortolserine (Q=o-tolyl; E=CH₂C₆H₅; Z═N—CH₂C₆H₅);cymserine (Q=p-isopropylphenyl; E=CH₃; Z═N—CH₃); N¹-benzylnorcymserine(Q=p-isopropylphenyl; E=CH₃; Z═N—CH₂—C₆H₅); N¹-phenethylnorcymserine(Q=p-isopropylphenyl; E=CH₃; Z═N—CH₂—CH₂—C₆H₅); N¹-norcymserine(Q=p-isopropylphenyl; E=CH₃; Z═N—H); N⁸-benzylnorcymserine(Q=p-isopropylphenyl; E=N—CH₂—C₆H₅; Z═N—CH₃); N⁸-phenethylnorcymserine(Q=p-isopropylphenyl; E=N—CH₂CH₂C₆H₅; Z═NCH₃); N⁸-norcymserine(Q=p-isopropylphenyl; E=H; Z═N—CH₃); N¹,N⁸-bisnorcymserine(Q=p-isopropylphenyl; E=H; Z═N—H); (−)-N¹,N⁸-bisbenzylnorcymserine(Q=p-isopropylphenyl; E=CH₂C₆H₅; Z═N—CH₂C₆H₅); thiacymserine(Q=p-isopropylphenyl; E=CH₃; Z═S); thiatolserine (Q=o-tolyl; E=CH₃;Z═S).

Donepezil hydrochloride, rivastigmine hydrogen (2R,3R)-tartrate andgalantamine hydrobromide are the preferred AChEIs, phenserine tartrateand huperzine A also being advantageous AChEIs, for improving dementiasof Alzheimer's type according to the present invention. Specifically,all the donepezil, rivastigmine, galantamine phenserine and huperzine Asalts solvates, analogs, derivatives and prodrugs are AChEIs useful forthe method of the present invention.

According to the present invention, an AChEI, when used at a dose whichis from 2.5 to 7 times the maximum recommended dose in a patientsuffering from Alzheimer type dementia, in combination with a nsPAChA atthe aforementioned doses, is well tolerated and is found in the blood ofsaid patients at levels that are much higher than those expected for theadministered doses, such that 2.5 times the maximum recommended dose ofan AChEI are sufficient to induce neuroprotection. However, the presentinvention contemplates the safe administration of even higher doses ofsaid AChEI assuring a substantially increased supply of acetylcholine inthe CNS with consequent ability to combat neurodegeneration in saidpatient.

Among the preferred AChEIs, donepezil or a pharmaceutically acceptablesalt thereof, in particular donepezil hydrochloride at a dose of from 25mg to 151 mg rivastigmine or a pharmaceutically acceptable salt thereof,in particular rivastigmine hydrogen tartrate at a daily oral dose, inrivastigmine, of from 30 mg to 84 mg or at a daily transdermal dose, inrivastigmine, of from 30 mg/24 hours to 93 mg/24 hours; and galantamineor a pharmaceutically acceptable salt thereof, in particular galantaminehydrobromide at a dose, in galantamine, of from 60 mg to 224 mg; andhuperzine A at a dose of from 0.45 mg to 4.8 mg; give very high bloodlevels assuring neuroprotection, when a nsPAChA is concurrently orsequentially administered therewith at a daily dose which is from morethan 200% to 800% the dose of said nsPAChA used in the anticholinergictherapy. In particular, said nsPAChA is selected from the groupconsisting of pharmaceutically acceptable salts of trospium,pharmaceutically acceptable salts of glycopyrrolium, solifenacin andpharmaceutically acceptable salt thereof and propiverine andpharmaceutically acceptable salt thereof.

According to an advantageous embodiment, said AChEI is donepezilhydrochloride, administered at a daily dose of from 25 mg to 151 mg andsaid nsPAChA is solifenacin succinate, administered at a daily dose offrom 21 mg to 80 mg.

According to another advantageous embodiment, said AChEI is galantamine,as hydrobromide, administered at a daily dose of from 60 mg to 224 mg,and said nsPAChA is propiverine, as hydrochloride, administered at adaily dose of from 61 mg to 240 mg.

According to a further advantageous embodiment, said AChEI isrivastigmine, as hydrogen tartrate, administered at a daily dose of from30 mg to 93 mg, and said nsPAChA is selected from the group consistingof trospium chloride, administered at a daily dose of from 80 mg to 480mg; propiverine hydrochloride, administered at a daily dose of from 61mg to 240 mg; and solifenacin succinate, administered at a daily dose offrom 21 mg to 80 mg.

The AChEIs are administered in pharmaceutical compositions wherein theactive ingredient is in admixture with a pharmaceutical carrier. Saidcompositions may be those which are found in the commercial, brand orgeneric products.

In view of the high doses which can be administered according to thepresent invention, the AChEI may be formulated in new compositions. Forexample, donepezil hydrochloride may be orally administered once a dayin a composition, comprising said donepezil hydrochloride in an amountof from 25 mg to 151 mg, in admixture with a pharmaceutical carrier;rivastigmine may be orally administered twice per day in a compositioncomprising rivastigmine hydrogen tartrate, in an amount in rivastigmineof from 15 mg to 42 mg, in admixture with a pharmaceutical carrier in anIR formulation; and galantamine may be orally administered twice per dayin a composition comprising galantamine hydrobromide, in an amount ingalantamine of from 40 mg to 112 mg in admixture with a pharmaceuticalcarrier in an IR formulation, or once a day in a pharmaceuticalcomposition comprising galantamine hydrobromide in an amount ingalantamine of from 60 mg to 224 mg in admixture with a pharmaceuticalcarrier in an ER formulation.

As set forth above, an overdose of an AChEI may be administered to apatient suffering from Alzheimer type dementia without concurrentcholinergic adverse effects by concomitantly administering an nsPAChA,at the aforementioned dose, to said patient, the sole remaining adverseeffect being nausea/vomiting. This adverse effect may be alleviated byadministration of a non-anticholinergic antiemetic agent (naAEA).

Any antiemetic agent substantially devoid of central anticholinergiceffects may be used in order to block emesis due to the overdoses ofAChEIs which are administered according to the present invention. A listof typical naAEAs adapted to this use is reported in WO 2011/034568.Advantageous naAEAs are domperidone, at a daily dose of from 10 mg to 80mg, metoclopramide, at a daily dose of from 10 mg to 60 mg, aprepitant,at a dose of from 40 mg to 125 mg; alosetron, orally administered in0.5-mg or in 1-mg tablets at a dose of 0.5-1 mg, once or twice a day;dolasetron mesylate, orally administered in 50-mg or in 100-mg tablets,at a daily dose of 100 mg; granisetron, orally administered orally in1-mg or in 2-mg tablets, at a dose of 1 mg twice a day or 2 mg once aday, or parenterally administered in a 3-mg/1-ml solution for i.m.injection or in a 3 mg/3-ml solution for i.v. injection; ondansetron,orally administered in 4-mg or in 8-mg tablets at a dose of from 4 mg to24 mg; palonosetron, administered in a 0.25-mg/5-ml solution byintravenous injection at a dose of 0.25 mg; ramosetron, orally orintravenously administered at a dose of 5 mg; and tropisetron,administered either intravenously in a 2-mg/2-ml or 5-mg/5-ml solutionat a dose of 2 mg or 5 mg, or orally administered in a 5-mg capsule at adose of 5 mg; the above doses being referred to their contents in5-HT3-antagonist's base, unless otherwise specified.

C. The Fixed-Dose Combinations

As mentioned above, the nsPAChA may be formulated in a pharmaceuticalcomposition also containing an AChEI.

Thus, the present invention also provides a pharmaceutical unit formparticularly useful for inducing high and even very high bloodconcentrations of the AChEI in a human being, which comprises

(a) a nsPAChA selected from the group consisting of solifenacin,pharmaceutically acceptable salts of solifenacin, propiverine,pharmaceutically acceptable salts of propiverine, trospium quaternarysalts, clidinium quaternary salts, benzilonium quaternary salts andglycopyrronium quaternary salts, in an amount of from more than 200% to800% the maximum amount contained in the commercial products for theanticholinergic therapy; and

(b) an AChEI selected from the group consisting of(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one(donepezil) and pharmaceutically acceptable salts thereof,(S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate(rivastigmine) and pharmaceutically acceptable salts thereof,4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol(galantamine) and pharmaceutically acceptable salts thereof, and(1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0^(2,7)]trideca-2(7),3,10-trien-5-one(huperzine A), in an amount of from 2.5 to 7 times the maximum amountcontained in the commercial products for the treatment of Alzheimer typedementia.

Preferred Component (a) is a pharmaceutically acceptable salt oftrospium, especially trospium chloride, succinate, maleate, fumarate ortartrate, a pharmaceutically acceptable salt of solifenacin, especiallyits compound with succinic acid 1:1 (solifenacin succinate), apharmaceutically acceptable salt of propiverine, especially itshydrochloride, a pharmaceutical acceptable salt of glycopyrronium,especially glycopyrronium bromide; a pharmaceutically acceptable salt ofoxyphencyclimine, especially its hydrochloride or a pharmaceuticallyacceptable salt of tolterodine, especially its L-hydrogen tartrate.

Preferred Components (b) are donepezil hydrochloride, rivastigminehydrogen tartrate, galantamine hydrobromide; and huperzine A.

More particularly, the nsPAChA Component (a) is selected from the groupconsisting of trospium chloride, in an amount of from 42 mg to 480 mg,advantageously from 50 mg to 480 mg, preferably from 60 mg to 480 mg perdosage unit, solifenacin succinate, in an amount of from 21 mg to 80 mg,advantageously from 22.5 mg to 80 mg, preferably from 25 mg to 80 mg perdosage unit; and propiverine hydrochloride in an amount of from 31.5 mgto 240 mg, advantageously from 32.25 mg to 240 mg, preferably from 35 mgto 240 mg per dosage unit. A Component (a) selected from the groupconsisting trospium chloride, in an amount of from 42 to 160 mg,preferably from 60 mg to 160 mg, in an IR formulation; glycopyrroniumbromide, in an amount of from 4.1 to 16 mg, preferably from 4.5 to 12 mgin an IR formulation; propiverine hydrochloride, in an amount of from31.5 mg to 120 mg, preferably from 35 mg to 120 mg, in an IRformulation, trospium chloride, in an amount of from 126 mg to 480 mg,preferably from 160 mg to 480 mg, in an ER formulation; and propiverinehydrochloride, in an amount of from 61.5 mg to 240 mg, preferably from65 mg to 240 mg, in an ER formulation; is particularly advantageous.

The AChEI Component (b) is selected from the group consisting ofdonepezil hydrochloride, in an amount of from 25 mg to 151 mg,preferably from 57.5 to 151 mg, per dosage unit; rivastigmine, as thehydrogen tartrate thereof, in an amount of from 15 mg to 93 mg,preferably from 24 mg to 93 mg per dose unit; galantamine, as thehydrobromide thereof, in an amount of from 40 to 224 mg per dose unit;and huperzine A, in an amount of from 150 μg to 1.2 mg, preferably from200 μg to 1.2 mg per dose unit. A Component (b) selected from the groupconsisting of rivastigmine (as hydrogen tartrate) in an IR oralformulation comprising from 15 mg to 42 mg of active ingredient;galantamine (as hydrobromide), in an IR formulation comprising from 40mg to 112 mg of active ingredient; rivastigmine (as hydrogen tartrate),in an ER patch formulation releasing from 30 mg/24 hours to 93 mg/24hours of active ingredient; and galantamine (as hydrobromide) in an ERformulation comprising from 60 mg to 168 mg of active ingredient; isparticularly advantageous.

The unit form of the present invention may be a tablet, a capsule, apre-measured volume of a liquid solution or suspension for oraladministration or a patch for transdermal application. In said unit formthe nsPAChA and the AChEI may be mixed together or separated accordingto known technologies in admixture with a pharmaceutical carrier in apharmaceutical composition.

Component (a) and Component (b) are formulated with conventionalpharmaceutical carriers in known formulations for oral use wherein saidcomponents are mixed together or separated, for example in two tabletsintroduced in a capsule or in a two-compartment capsule or in amultilayer (di-layer) tablet wherein the two components are both in IRor in ER form or one of the two components is in IR form and the otheris in ER form, according to known technologies.

The pharmaceutical carriers and vehicles are those commonly used for thepreparation of compositions for oral, buccal and parenteral, inparticular transdermal, administration. Appropriate unit forms comprisethe oral forms such as tablets, soft or hard gelatin capsules, powdersor granulates in sachets and suitably measured oral solutions orsuspensions as well as patches for transdermal administration.

Component (a) and component (b) may also be present in form of one oftheir complexes with a cyclodextrin, for example α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin ormethyl-β-cyclodextrin.

Component (a) and component (b) may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or additives.

For oral administration, Component (a) and Component (b), together orseparately, are formulated by mixing the active ingredient withconventional pharmaceutical acceptable carriers enabling said activeingredients to be formulated in tablets, dragees, orally disintegratingtablets, capsules, liquid solutions or suspensions, syrups and the like.

Carriers for IR tablets include for example starches, cellulose andderivatives thereof; lubricants such as talc, stearic acid or magnesiumstearate; diluents such as talc, powdered cellulose, lactose, starchessuch as maize or corn starch, mannitol, sorbitol; disaggregating agentssuch as microcrystalline cellulose or crospovidone; lubricants such aspolyethylenglycol or magnesium stearate; ligands such asmethylcellulose, sodium carboxymethylcellulose, alginic acid, alginates;sweeteners, such as saccharose, dextrose, mannitol, saccharin; orflavoring agents such as natural or synthetic oils.

Carriers for orally disintegrating tablets include for examplelubricants, aggregating, sweetening, flavoring or disaggregating agentsas well as agents improving the buccal mucosa absorption of components(a) and (b) such as sorbitol, mannitol, lactose and cellulose.

Carriers for liquid, normally aqueous, suspensions or solutions includefor example antioxidants, such as sodium metabisulfite or sodiumsulfite, thickening agents, such as microcrystalline cellulose,hydroxypropylcellulose, carboxymethylcellulose or polyvinylpyrrolidone,preservatives such as methyl paraben, ethyl paraben, sodiumethylenediaminotetracetate, sodium benzoate or an alkaline salt ofsorbic acid, as well as flavoring and sweetening agents.

The sweeteners contained in the orally disintegrating tablets and theliquid suspensions or solutions may be natural, optional reduced sugarssuch as sucrose, dextrose, xylitol, mannitol or sorbitol, or syntheticproduct such as sodium saccharine or aspartame.

The flavoring agents are pharmaceutically acceptable flavors and tastesof synthetic and natural oils, the latter extracted from plants, leaves,flowers, fruits and their combinations, such as cinnamon, peppermint,anise and citron leaves, bitter almond, citrus fruits, in particularorange and/or lemon, linden and grapefruit oils. Also chocolate, vanillaor eucalyptus flavor and essences of fruit, in particular apple, pear,peach, strawberry, cherry, apricot, orange, lemon and grapes may beadvantageously used.

The composition according to the present invention may be in form of acapsule containing two tablets as described herein above, one of themcomprising Component (a) and the other comprising Component (b).

The association nsPAChA/AChEI may be formulated in tablets in which oneor both of the two components is in controlled-release formulation, forexample as a dispersion of said component in hydroxypropyl methylcellulose or in a film-coated microgranule. Advantageously, the AChEI,in a ER-formulation is in the core and the nsPAChA, in IR-formulation,is in the outer layer in multi-layer tablets in which, for example, boththe core and the outer layer are coated with a film. Analogously,capsules made of two separated parts, one containing Component (a), inIR- or ER-formulation and the other containing Component (b), in IR- orER-formulation, may be used

Carriers and vehicles for ER tablets include retardant materials such asis acrylic and methacrylic acid polymers and copolymers; cellulosederivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylethylcellulose, hydroxypropylcelluloses, methylcellulose,ethylcellulose, or sodium carboxymethylcellulose; gums; waxes;glycerides or aliphatic alcohols or a mixture thereof.

In particular, the unit forms of the present invention comprise a memberselected from the group consisting of trospium chloride, solifenacinsuccinate and propiverine hydrochloride, as an nsPAChA and a memberselected from the group consisting of donepezil hydrochloride, in anamount of from 25 mg to 151 mg; rivastigmine hydrogen tartrate; in anamount in rivastigmine of from 15 mg to 42 mg; galantamine hydrobromide,in an amount in galantamine of from 40 to 112 mg; and huperzine A, in anamount of from 150 μg to 1.2 mg as an AChEI.

According to an embodiment, the compositions of the present inventionare formulated by mixing the Component (a) and the Component (b)together, in admixture with a pharmaceutical carrier for an immediate orextended release and are useful for inducing neuroprotection in apatient suffering from a dementia of Alzheimer type treated with saidAChEI.

An advantageous composition according to this embodiment comprises from42 mg to 160 mg preferably from 80 mg to 160 mg; of trospium chloride,as Component (a); and

-   -   from 15 mg to 42 mg, preferably form 18 mg to 42 mg, of        rivastigmine (as hydrogen tartrate); or    -   from 40 mg to 84 mg preferably from 42 mg to 84 mg, of        galantamine (as hydrobromide), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

Another advantageous composition according to this embodiment comprises

-   -   from 21 mg to 80 mg, preferably from 25 mg to 80 mg, of        solifenacin succinate, as Component (a); and    -   from 25 mg to 70 mg, preferably from 40 mg to 70 mg, of        donepezil hydrochloride, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A particular composition according to this embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   from 40 mg to 60 mg of donepezil hydrochloride, as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A further advantageous composition according to this embodimentcomprises

-   -   from 31.5 mg to 120 mg, preferably from 35 mg to 120 mg of        propiverine hydrochloride, as Component (a); and    -   from 15 mg to 42 mg, preferably form 18 mg to 42 mg, of        rivastigmine (as hydrogen tartrate); or    -   from 40 mg to 112 mg preferably from 42 mg to 112 mg, of        galantamine (as hydrobromide), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A particular composition according to this embodiment comprises

-   -   35 mg of propiverine hydrochloride, as Component (a); and    -   25 mg of rivastigmine (as hydrogen tartrate), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

Another particular composition according to this embodiment comprises

-   -   75 mg of propiverine hydrochloride, as Component (a); and    -   60 mg of galantamine (as hydrobromide), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

According to another embodiment, the compositions of the presentinvention are formulated by mixing the Component (a) with apharmaceutical carrier for an immediate or extended release in tablets(Tablet A) and the Component (b), separately, with a pharmaceuticalcarrier for an immediate or extended release in tablets (Tablet B) andintroducing Tablet A and Tablet B in a capsule for oral administrationas described for example in GB 1204580 or in US 2007/0224259.

An advantageous composition according to this embodiment consists ofsoft or hard gelatin capsules each containing

-   -   Tablet A comprising from 31.5 mg to 40 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation; and    -   Tablet B, comprising from 25 mg to 35 mg of rivastigmine (as        hydrogen tartrate); as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

Another advantageous composition according to this embodiment consistsof soft or hard gelatin capsules each containing

-   -   Tablet A comprising from 4.1 mg to 16 mg of glycopyrrolium        bromide, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation; and    -   Tablet B, comprising from 25 mg to 42 mg of rivastigmine (as        hydrogen tartrate); as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A further advantageous composition according to this embodiment consistsof soft or hard gelatin capsules each containing

-   -   Tablet A comprising from 6 mg of glycopyrrolium bromide, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, 30 mg of rivastigmine (as hydrogen tartrate); as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

According to a further embodiment, the compositions according to thepresent invention are formulated in a di-layer tablet which releases twodrug doses, in which the release of a drug from one drug-containinglayer does not interfere with the release of a drug from the otherdrug-containing layer as described for example in WO 2006/089493. Anadvantageous composition according to this embodiment consists of

-   -   Layer A, comprising from 21 mg to 40 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation and    -   Layer B, comprising from 25 mg to 50 mg of donepezil        hydrochloride, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

Another embodiment of the present invention provides unit formsconsisting of tablets comprising

-   -   from 21 mg to 40 mg, of solifenacin succinate, as Component (a);        and    -   from 25 mg to 50 mg preferably from 37.5 mg to 50 mg, of        donepezil hydrochloride;        as Component (b),        in admixture with a pharmaceutical carrier in a IR-formulation        for oral administration.

According to a preferred embodiment, the invention provides unit formsconsisting of tablets comprising

-   -   25 mg of solifenacin succinate, as Component (a) and    -   from 25 mg to 50 mg preferably from 37.5 mg to 50 mg, of        donepezil hydrochloride, as Component (b),        in admixture with a pharmaceutical carrier, in a formulation for        oral administration to be administered once a day.

Another preferred embodiment of the invention provides unit forms fororal administration consisting of tablets comprising

-   -   from 21 mg to 80 mg of solifenacin succinate, as Component (a)        and    -   from 25 mg to 151 mg preferably from 57.5 mg to 151 mg, of        donepezil hydrochloride, as Component (b),        in admixture with a pharmaceutical carrier, in a formulation for        oral administration to be administered once a day.        III. A Third Aspect of the Present Invention

In a third aspect, the present invention provides an improved method toaugment and extend the efficacy of conventional cholinergic therapiesfor Alzheimer type dementias by mitigating the common dose-limitingadverse events of cholinomimetic treatments of said Alzheimer typedementias that arise as a result of the concomitant excessivestimulation of cholinergic receptors in the PNS. Drugs that act toselectively inhibit the activation of all or nearly all the muscarinicreceptors in the PNS, but not in the CNS, resulting from cholinomimetictherapy have the potential to reduce the adverse effects, such thathigher cholinomimetic doses can be administered leading to greater andmore prolonged antidementia efficacy with fewer peripherally mediatedside effects. By combining an extended release cholinomimetic with aperipheral anticholinergic having an advantageous duration ofpharmacologic action, in a single dosage form, the benefits to patientsof an even longer duration of action is also achieved.

In particular, the invention provides a method for increasing AChEIblood levels in a human being, which comprises administering said humanbeing an AChEI dose which is at least 2.5, up to 7 times higher than thedose used in the treatment of Alzheimer type dementias, in combinationwith a nsPAChA dose which is at least as high as, advantageously atleast twice, preferably more than twice up to 8 times higher than thedose used in the anticholinergic therapy.

More particularly, the invention provides a method for increasing theblood levels of an AChEI in a human subject which comprisesadministering to said subject a nsPAChA selected from the groupconsisting of solifenacin, pharmaceutically acceptable salts andcompounds of solifenacin, pharmaceutically acceptable salts of trospium,pharmaceutically acceptable salts of glycopyrrolium, propiverine andpharmaceutically acceptable salts of propiverine, said nsPAChA beingadministered at a dose which is at least as high as, up to eight timesthe dose used for the anticholinergic therapy, advantageously at a doseof from more than twice to eight times, preferably from 2.5 to 8 timesthe dose used for the anticholinergic therapy, in combination with adose of said AChEI which is from 2.5 to 7 times the dose used for thetreatment of Alzheimer type dementia. Said human subject may be apatient suffering from dementia of Alzheimer type. The pharmaceuticallyacceptable salts of propiverine and solifenacin include the propiverineand solifenacin quaternary salts, in particular the methyl chloride, themethyl iodide and the methyl bromide thereof.

This finding is surprising because an increase in blood levels of a drugnormally also increases the risk of side effects while, in the case ofthe combined nsPAChA/AChEI treatment according to the present invention,the most common and dangerous adverse effects are in fact suppressed.

The present invention also provides a pharmaceutical compositioncomprising, as an active ingredient, an nsPAChA selected from the groupconsisting of solifenacin and pharmaceutically acceptable salts thereof,propiverine and pharmaceutically acceptable salts thereof, and trospiumpharmaceutically acceptable salts, in an amount which is from 100% to800% the maximum amount of said nsPAChA contained in compositionsindicated for the anticholinergic therapy, for use for increasing theAChEI blood levels in a human treated with an AChEI dose which is from250% to 700% the maximum recommended dose of said AChEI.

A. The nsPAChAs

Advantageously, the used nsPAChAs are quaternary ammonium nsPAChAs,sulfonium nsPAChAs, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-iso-quinolinecarboxylate (solifenacin) andits pharmaceutically acceptable salts, (1-methylpiperidin-4-yl)2,2-di(phenyl)-2-propoxyacetate (propiverine) and its pharmaceuticallyacceptable salts, 1,4,5,6-tetrahydro-1-methylpyrimidin-2-ylmethylα-cyclohexyl-α-hydroxy-α-phenylacetate (oxyphencyclimine) and itspharmaceutically acceptable salts,(R)—N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine(tolterodine) and its pharmaceutically acceptable salts. Said nsPAChAs,preferably, are compounds with duration of action of at least 6 hours,advantageously from 8 to 24 hours, more advantageously from 10 to 24hours, preferably from 12 to 24 hours, even though nsPAChAs having anappropriate duration of action corresponding to the duration of actionof the concomitantly administered AChEI may be successfully used.

Particularly advantageous quaternary ammonium nsPAChAs or sulfoniumnsPAChAs are compounds of formula II

wherein

-   -   R is a radical selected from the group consisting of those of        formulas (a)-(e)

-   -   -   A being methyl and A′ being (C₁-C₄)alkyl or 2-fluoroethyl            group or A and A′ forming a 1,4-butylene or 1,5-pentylene            chain, L being hydrogen or methoxy, Alk and Alk′ each being            (C₁-C₄)alkyl and Y being a bivalent radical selected from            the group consisting of 1,2-ethylene, 1,3-propylene,            1,4-butylene and 2-oxa-1,3-propylene; the corresponding            counter ion being a pharmaceutically acceptable anion, such            as a chloro, bromo, iodo, tartrate, hydrogen tartrate,            succinate, maleate, fumarate, sulfate, hydrogen sulfate or            methylsulfate anion;

    -   n and m, independently, are zero or 1;

    -   X is a (C₂-C₃)alkylene group;

    -   R₁ and R₂ are each phenyl, cyclopentyl, cyclohexyl,        1-cyclohexenyl, 2-thienyl and, when R is a radical (a), also        each represents (C₁-C₄)alkyl;

    -   R₃ is H or OH or, only when R is a radical (a), also a COOAlk        group, Alk being a (C₁-C₄)alkyl group.

Exemplary nsPAChAs of formula II above used for preparing medicamentsfor the treatment of Alzheimer type dementia in combination with AchEIsare

-   -   anisotropine methylbromide [R=(a), A=A′=CH₃, L=H; n=1; m=0;        R₁═R₂=n-C₃H₇; R₃═H;];    -   ciclotropium bromide [R=(a), A=CH₃, A′=isopropyl, L=H; n=1; m=0;        R₁=phenyl; R₂=cyclopentyl; R₃═H];    -   flutropium bromide [R=(a), A=CH₃, A′=2-fluoroethyl, L=H; n=1;        m=0; R₁═R₂=phenyl; R₃═OH];    -   homatropine methylbromide [R=(a), A=A′=CH₃, L=H; n=1; m=0;        R₁=phenyl; R₂═R₃═H];    -   sintropium bromide; [R=(a), A=CH₃, A′=isopropyl, L=H; n=1; m=0;        R₁═R₂=n-C₃H₇; R₃═H];    -   tematropium metilsulfate [R=(a), A=A′=CH₃, L=H; n=1; m=0;        R₁=phenyl; R₂═COOC₂H₅; R₃═H];    -   tropenziline bromide [R=(a), A=A′=CH₃, L=methoxy; n=1; m=0;        R₁═R₂=phenyl, R₃═OH];    -   trospium chloride [R=(a), A+A′=1,4-butylene, L=H; n=1; m=0;        R₁═R₂=phenyl; R₃═OH];    -   clidinium bromide [R=(b)-3-, Alk=methyl; n=1; m=0; R₁═R₂=phenyl;        R₃═OH];    -   droclidinium bromide [R=(b)-3-, Alk=methyl; n=1; m=0; R₁=phenyl;        R₂=cyclopentyl; R₃═OH];    -   benzilonium bromide [R=(c)-3-, both Alk and Alk′=ethyl; n=1;        m=0; R₁═R₂=phenyl; R₃═OH];    -   benzopyrronium bromide [R=(c)-3-, both Alk and Alk′=methyl; n=1;        m=0; R₁═R₂=phenyl; R₃═OH];    -   cyclopyrronium bromide [R=(c)-3-, Alk=methyl and Alk′=ethyl;        n=1; m=0; R₁=phenyl; R₂=cyclopentyl; R₃═H];    -   glycopyrronium bromide (glycopyrrolate) [R=(c)-3-, both Alk and        Alk′=methyl; n=1; m=0; R₁=phenyl; R₂=cyclopentyl; R₃═H];    -   heteronium bromide [R=(c)-3-, both Alk and Alk′=methyl n=1; m=0;        R₁=phenyl; R₂=2-thienyl; R₃═OH];    -   hexopyrronium bromide [R=(c)-3-, both Alk and Alk′=methyl; n=1;        m=0; R₁=phenyl; R₂=cyclohexyl; R₃═H];    -   oxypyrronium bromide [R=(c)-2-, both Alk and Alk′=methyl; n=1;        m=1; X=1,2-ethylene; R₁=phenyl; R₂=cyclohexyl; R₃═OH];    -   ritropirronium bromide [R=(c)-3-, both Alk and Alk′=methyl; n=1;        m=0; R₁=phenyl; R₂=cyclopentyl; R₃═OH];    -   etipirium iodide [R=(d), Alk=methyl, Y=1,2-ethylene; n=1; m=1;        X=1,2-ethylene; R₁═R₂=phenyl; R₃═OH];    -   fenclexonium methylsulfate [R=(d), Alk=CH₃, Y=1,3-propylene;        n=0; m=1; X=1,2-ethylene; R₁=phenyl; R₂=1-cyclohexenyl; R₃═H];    -   tricyclamol chloride (procyclidine methochloride) [R=(d),        Alk=methyl, Y=1,2-ethylene; n=0; m=1; X=1,2-ethylene; R₁=phenyl;        R₂=cyclohexyl; R₃═OH];    -   tiemonium iodide [R=(d), Alk=methyl, Y=2-oxa-1,3-propylene; n=0;        m=1; X=1,2-ethylene; R₁=phenyl; R₂=2-thienyl; R₃═OH];    -   hexasonium iodide [R=(e); n=1; m=1; X=1,2-ethylene; R₁=phenyl;        R₂=cyclohexyl; R₃═H]; and    -   oxysonium iodide [R=(e); n=1; m=1; X=1,2-ethylene; R₁=phenyl;        R₂=cyclohexyl; R₃═OH.

A nsPAChA selected from the group consisting of(1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (solifenacin) or apharmaceutically acceptable salt or compound thereof,1-methyl-4-[(2,2-diphenyl-2-n-propoxy)acetoxy]piperidine (propiverine)and pharmaceutically acceptable salts thereof,3-(2-hydroxy-2,2-diphenylacetoxy)-spiro[bicyclo[3.2.1]octane-8,1′-pyrrolidin]-1′-ium(trospium) pharmaceutically acceptable salts, and3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium(glycopyrrolium) pharmaceutically acceptable salts, are particularlyadvantageous.

Solifenacin and pharmaceutically acceptable salts and compounds thereof,including the quaternary ammonium salts thereof, and their preparationare described in U.S. Pat. No. 6,017,927. Methods for the preparationand for the purification of solifenacin and its salts, in particular ofsolifenacin succinate, are described for example in WO 2007/076116, WO2009/139002, WO 2011/003624 and WO 2012/001481.

Propiverine and pharmaceutically acceptable salts thereof, in particularits hydrochloride, are described in DD 106643, CN 1285348, CN102218063(A), KR 2005-0011138, KR 2005-0011139, KR20110111782 (A) and inWO 2011/114195. The propiverine quaternary salts, i.e. the (C1-C4)alkylpropiverinium halides may be prepared by reacting1-methyl-4-[(2,2-diphenyl-2-propoxy)acetoxy]piperidine (propiverinebase) with a (C1-C4)alkyl halide (chloride, bromide or iodide), thepropiverine base starting material being also obtained as crude productas described in WO 2011/114195 or by hydrolysis of propiverinehydrochloride, which is an easily available commercial product alsoobtainable for example as described in DD 106643, CN 1285348, CN102218063(A) KR 2005-0011138, KR 2005-0011139, KR20110111782 (A) or inthe aforesaid WO 2011/114195. In practice, an aqueous suspension ofpropiverine hydrochloride is treated with an inorganic base and crudepropiverine base is recovered by extraction from an organic solvent andevaporation of the solvent; and the residue is treated with a(C1-C4)alkyl (preferably methyl) halide (chloride, bromide or iodide) inan alcoholic solution and the1-alkyl-1-methyl-4-[(2,2-diphenyl-2-propoxy)acetoxy]piperidinium halidewhich precipitates is isolated.

Trospium pharmaceutically acceptable salts, in particular its chloride,may be prepared as described in U.S. Pat. No. 3,480,626 and othertrospium pharmaceutically acceptable salts, in particular the tartrate,maleate, fumarate and succinate salts thereof, are cited in US2006/0293356.

Glycopyrronium pharmaceutical acceptable salts, in particular thebromide, are obtainable according to U.S. Pat. No. 2,956,062.

Trospium is a long-acting nsPAChA whose absorbed amount has an averageplasma half-life of about 18 hours. Also solifenacin succinate is annsPAChA having long-acting characteristics, its half-life being verylong, especially following long-term administration.

Also other quaternary ammonium salts or sulfonium salts of formula IIabove, such as homatropine quaternary salts, anisotropine quaternarysalts, clidinium quaternary salts, benzilonium quaternary salts aresuitable nsPAChAs, but their half-life is short.

According to the present invention, in order to increase AChEI bloodlevels, the nsPAChAs are concurrently or sequentially administered withthe above AChEIs, at a daily dose which is from 100% to 800% the dose ofsaid nsPAChA used in the anticholinergic therapy.

According to a preferred embodiment, trospium chloride, at daily dosesof from 40 mg to 320 mg in an IR formulation or from 60 mg to 480 mg inan ER formulation; solifenacin succinate, at daily doses of from 10 mgto 80 mg in an IR formulation; propiverine hydrochloride, at daily dosesof from 30 mg to 240 mg in an IR or ER formulation; and glycopyrrolium,at daily doses of from 8 mg to 64 mg, in IR or ER formulation, allow theadministration of AChEI doses that are from 2.5 to 4, up to 7 timeshigher than their maximum recommended daily doses, in order to inducevery high AChEI blood levels, not attainable with hypothetical identicaldoses of AChEI, administered alone or in combination with lower doses ofnsPAChA.

In particular, the aforementioned daily doses of trospium chloride,solifenacin succinate, propiverine hydrochloride or glycopyrroliumbromide allow the safe administration of donepezil hydrochloride at adaily dose of from 25 mg to 151 mg; of rivastigmine hydrogen tartrate,at a daily dose of from 30 mg to 126 mg; and galantamine hydrobromide,at a daily dose of from 60 mg to 224 mg and huperzine A, at a dose up to4.8 mg, without inducing the most dangerous adverse effects of saidAChEI.

For the intended use, the nsPAChA is formulated in pharmaceuticalcompositions comprising, as an active ingredient thereof, said nsPAChAin admixture with a pharmaceutical carrier.

In brand or generic nsPAChAs used in the anticholinergic therapy, forexample, anisotropine hydrobromide is available in unit forms at themaximum dose of 50 mg; butylscopolamine bromide is available in unitforms at the maximum dose of 20 mg; cimetropium bromide is available inunit forms at the maximum dose of 50 mg; clidinium bromide, is availablein unit forms, also comprising 2.5 mg chlordiazepoxide, at the maximumdose of 5 mg; glycopyrrolium bromide is available in unit forms at themaximum dose of 2 mg; otilonium bromide is available in unit forms atthe maximum dose of 40 mg; prifinium bromide is available in unit formsat the maximum dose of 60 mg; propiverine hydrochloride is available inIR unit forms at the maximum dose of 15 mg and in a ER unit form at themaximum dose of 30 mg; solifenacin succinate is available in unit formsat the maximum dose of 10 mg; timepidium bromide is available in unitforms at the maximum dose of 30 mg; trospium chloride is available in IRunit forms at the maximum dose of 20 mg and in ER unit form at themaximum dose of 60 mg; and valethamate bromide is available in unitforms, also comprising 325 mg paracetamol, at the maximum dose of 10 mg.

The pharmaceutical composition of the present invention, for use forinducing high and very high AChEI blood levels as illustrated above,contain an nsPAChA, for example selected from the group consisting ofthose mentioned in the preceding paragraph, at a dose of from 100% to800%%, preferably from 200% to 800%, the maximum dose defined in saidparagraph, in admixture with a pharmaceutical carrier.

For example, said pharmaceutical composition for inducing high an evenvery high AChEI levels, when administered to a human being treated witheven a single AChEI dose, comprises an nsPAChA selected from the groupconsisting of anisotropine hydrobromide, in an amount of from 50 mg to400 mg, preferably from 100 mg to 400 mg; butylscopolamine bromide, inan amount of from 20 mg to 160 mg, preferably from 40 mg to 160 mg;cimetropium bromide, in an amount of from 50 mg to 400 mg, preferablyfrom 100 mg to 400 mg; clidinium bromide, in an amount of from 5 mg to40 mg, preferably from 10 mg to 40 mg; glycopyrrolium bromide, in anamount of from 2 mg to 16 mg, preferably from 4 mg to 16 mg; otiloniumbromide, in an amount of from 40 mg to 320 mg, preferably from 80 mg to320 mg; prifinium bromide, in an amount of from 30 mg to 240 mg,preferably from 60 mg to 240 mg; propiverine hydrochloride, in an amountof from 15 mg to 240 mg, preferably from 30 mg to 240 mg; solifenacinsuccinate, in an amount of from 10 mg to 80 mg, preferably from 20 mg to80 mg; timepidium bromide, in an amount of from 30 mg to 240 mg,preferably from 60 mg to 240 mg; trospium chloride, in an amount of from20 mg to 480 mg, preferably from 40 mg to 480 mg; and valethamatebromide, in an amount of from 10 mg to 80 mg, preferably from 20 mg to80 mg; in admixture with a pharmaceutical carrier.

According to a preferred embodiment, the present invention provides apharmaceutical composition comprising, as an active ingredient, annsPAChA selected from the group consisting of glycopyrrolium bromide, inan amount of from 2 mg to 16 mg, preferably from 4 mg to 12 mg, in an IRformulation; glycopyrrolium bromide, in an amount of from 4 mg to 64 mg,preferably from 8 mg to 64 mg, in an ER formulation; trospium chloridein an amount of from 20 mg to 160 mg, preferably from 40 mg to 160 mg,in admixture with a pharmaceutical carrier in an IR formulation;trospium chloride in an amount of from 60 mg to 480 mg, preferably from120 mg to 480 mg, in admixture with a pharmaceutical carrier in an ERformulation; solifenacin succinate in an amount of from 10 mg to 80 mg,preferably from 20 mg to 80 mg, in admixture with a pharmaceuticalcarrier in an IR formulation; propiverine hydrochloride in an amount offrom 15 mg to 120 mg, preferably from 30 mg to 120 mg, in admixture witha pharmaceutical carrier in an IR formulation; and propiverinehydrochloride in an amount of from 30 mg to 240 mg, preferably from 60mg to 240 mg, in admixture with a pharmaceutical carrier in an ERformulation; for use for inducing high and even very high AChEI bloodlevels in a human subject treated with an overdose of said AChEI.

The aforementioned combination of the synergistic action of the nsPAChAs(peripheral only) and of the AChEI (both central and peripheral),inducing a theoretically infinite increase of the nsPAChA/AChEI pairdoses without untoward peripheral anticholinergic side effects, allowsthe attainment of very high blood levels of said AChEI. Thus, thesepharmaceutical compositions are useful for increasing AChEI blood levelsin human subjects, including a patient, suffering from Alzheimer typedementia, who is treated with a dose of said AChEI which is from 2.7 to7 times its maximal recommended dose, with a consequent bettertherapeutic response.

Thus, for example, the above pharmaceutical compositions containing annsPAChA, may be used in combination with donepezil or a pharmaceuticallyacceptable salt thereof, in particular donepezil hydrochloride at a doseof from 25 mg to 151 mg; rivastigmine or a pharmaceutically acceptablesalt thereof, in particular rivastigmine hydrogen tartrate, at a dose inrivastigmine of from 30 mg to 126 mg; and galantamine or apharmaceutically acceptable salt thereof, in particular galantaminehydrobromide, at a dose in galantamine, of from 60 mg to 224 mg, forinducing very high AChEI blood levels.

According to an advantageous embodiment, the pharmaceutical compositionsprepared by using the nsPAChAs according to the present invention arepresent in unit forms also containing other active ingredients, inparticular an AChEI at the aforementioned overdoses, to increase theAChEI blood levels in human subjects, in particular in a patientsuffering from a dementia Alzheimer type.

B. The AChEIs

Advantageous AChEIs are those currently used or tested for thisindication, such as 1,2,3,4-tetrahydro-9-acridinamine (tacrine),9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline (ipidacrine);(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one(donepezil) and its pharmaceutically acceptable salts, in particular thehydrochloride,3-[2-(1-benzyl-4-piperidyl)ethyl]-5,7,-dihydro-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one(icopezil) and its pharmaceutically acceptable salts, in particular themaleate,3-[1-benzylpiperdin-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)propan-1-one(zanapezil) and its pharmaceutically acceptable salts, in particular thefumarate, (S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenylcarbamate (rivastigmine) and its pharmaceutically acceptable salts, inparticular the hydrogen (2R,3R)-tartrate,4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol(galantamine) and its pharmaceutically acceptable salts, in particularthe hydrobromide;(1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0^(2,7)]trideca-2(7),3,10-trien-5-one(huperzine A) and phenserine and its analogs encompassed by the generalformula I

wherein Q is a phenyl group optionally substituted with a (C₁-C₄)alkylor with a methoxy group, Z is an oxygen or sulfur atom or a N-E′radical, E and E′, independently, are hydrogen or a methyl groupoptionally substituted with a phenyl or benzyl group; andpharmaceutically acceptable salts thereof.

Exemplary AChEIs of formula (I), described in U.S. Pat. No. 6,683,105,are phenserine (Q=phenyl; E=CH₃; Z═N—CH₃); (−)-N¹,N⁸-bisnorphenserine(Q=phenyl; E=H; Z═N—H); 4′-methoxyphenserine (Q=4′-methoxyphenyl; E=CH₃;Z═N—CH₃); (−)-N¹,N⁸-bisbenzylnorphenserine (Q=phenyl; E=CH₂C₆H₅;Z═N—CH₂C₆H₅); tolserine (Q=o-tolyl; E=CH₃; Z═N—CH₃);N¹-benzylnortolserine (Q=o-tolyl; E=CH₃; Z═N—CH₂—C₆H₅);N¹-phenethylnortolserine (Q=o-tolyl; E=CH₃; Z═N—CH₂—CH₂—C₆H₅);N¹-nortolserine (Q=o-tolyl; E=CH₃; Z═N—H); N⁸-benzylnortolserine(Q=o-tolyl; E=N—CH₂—C₆H₅; Z═N—CH₃); N⁸-phenethylnortolserine (Q=o-tolyl;E=N—CH₂—CH₂—C₆H₅; Z═N—CH₃); N⁸-nortolserine (Q=o-tolyl; E=H; Z═N—CH₃);N¹,N⁸-bisnortolserine (Q=o-tolyl; E=H; Z═N—H);(−)-N¹,N⁸-bisbenzylnortolserine (Q=o-tolyl; E=CH₂C₆H₅; Z═N—CH₂C₆H₅);cymserine (Q=p-isopropylphenyl; E=CH₃; Z═N—CH₃); N¹-benzylnorcymserine(Q=p-isopropylphenyl; E=CH₃; Z═N—CH₂—C₆H₅); N¹-phenethylnorcymserine(Q=p-isopropylphenyl; E=CH₃; Z═N—CH₂—CH₂—C₆H₅); N¹-norcymserine(Q=p-isopropylphenyl; E=CH₃; Z═N—H); N⁸-benzylnorcymserine(Q=p-isopropylphenyl; E=N—CH₂—C₆H₅; Z═N—CH₃); N⁸-phenethylnorcymserine(Q=p-isopropylphenyl; E=N—CH₂CH₂C₆H₅; Z═NCH₃); N⁸-norcymserine(Q=p-isopropylphenyl; E=H; Z═N—CH₃); N¹,N⁸-bisnorcymserine(Q=p-isopropylphenyl; E=H; Z═N—H); (−)-N¹,N⁸-bisbenzylnorcymserine(Q=p-isopropylphenyl; E=CH₂C₆H₅; Z═N—CH₂C₆H₅); thiacymserine(Q=p-isopropylphenyl; E=CH₃; Z═S); thiatolserine (Q=o-tolyl; E=CH₃;Z═S).

Donepezil hydrochloride, rivastigmine hydrogen (2R,3R)-tartrate andgalantamine hydrobromide are the preferred AChEIs, phenserine tartrateand huperzine A also being advantageous AChEIs, for improving dementiasof Alzheimer's type according to the present invention. Specifically,all the salts, solvates, analogs, derivatives and prodrugs of donepezil,rivastigmine, galantamine, phenserine and huperzine A are AChEIs usefulfor the method of the present invention.

According to the present invention, an AChEI, when used at a dose whichis from 2.5 to 7 times the maximum recommended dose in human subjects,in particular in a patient suffering from Alzheimer type dementia, incombination with a nsPAChA at the aforementioned doses, is welltolerated and is found in the blood of said subjects at levels that aremuch higher than those expected for the administered doses. However, thepresent invention contemplates the safe administration of even higherdoses of said AChEI assuring a substantially increased supply of AChEIin the CNS.

Among the preferred AChEIs, donepezil or a pharmaceutically acceptablesalt thereof, in particular donepezil hydrochloride at a dose of from 25mg to 151 mg; rivastigmine or a pharmaceutically acceptable saltthereof, in particular rivastigmine hydrogen tartrate at a dose, inrivastigmine, of from 30 mg to 126 mg; galantamine or a pharmaceuticallyacceptable salt thereof, in particular galantamine hydrobromide at adose, in galantamine, of from 60 mg to 224 mg; and huperzine A at a doseof from 0.45 mg to 4.8 mg; give very high AChEI blood levels when ansPAChA is concurrently or sequentially administered therewith at adaily dose which is from 100% to 800% the dose of said nsPAChA used inthe anticholinergic therapy. In particular, said nsPAChA is selectedfrom the group consisting of pharmaceutically acceptable salts oftrospium, solifenacin and pharmaceutically acceptable salt thereof andpropiverine and pharmaceutically acceptable salt thereof.

According to an advantageous embodiment, said AChEI is donepezilhydrochloride, administered at a daily dose of from 25 mg to 151 mg andsaid nsPAChA is solifenacin succinate, administered at a daily dose offrom 10 mg to 80 mg.

According to another advantageous embodiment, said AChEI is galantamine,as hydrobromide, administered at a daily dose of from 60 mg to 224 mg,and said nsPAChA is propiverine, as hydrochloride, administered at adaily dose of from 15 mg to 240 mg.

According to a further advantageous embodiment, said AChEI isrivastigmine, as hydrogen tartrate, administered at a daily dose of from30 mg to 126 mg, and said nsPAChA is selected from the group consistingof trospium chloride, administered at a daily dose of from 40 mg to 480mg; glycopyrrolium bromide, administered at a daily dose of from 8 mg to64 mg; propiverine hydrochloride, administered at a daily dose of from15 mg to 240 mg; and solifenacin succinate, administered at a daily doseof from 10 mg to 80 mg.

The AChEIs are administered in pharmaceutical compositions wherein theactive ingredient is in admixture with a pharmaceutical carrier. Saidcompositions may be those which are found in the commercial, brand orgeneric products.

In view of the high doses which can be administered according to thepresent invention, the AChEI may be formulated in new compositions. Forexample, donepezil hydrochloride may be orally administered once a dayin a composition, comprising said donepezil hydrochloride in an amountof from 25 mg to 151 mg, in admixture with a pharmaceutical carrier;rivastigmine may be orally administered twice per day in a compositioncomprising rivastigmine hydrogen tartrate, in an amount in rivastigmineof from 15 mg to 42 mg, in admixture with a pharmaceutical carrier in anIR formulation; and galantamine may be orally administered twice per dayin a composition comprising galantamine hydrobromide, in an amount ingalantamine of from 40 mg to 112 mg in admixture with a pharmaceuticalcarrier in an IR formulation, or once a day in a pharmaceuticalcomposition comprising galantamine hydrobromide in an amount ingalantamine of from 60 mg to 224 mg in admixture with a pharmaceuticalcarrier in an ER formulation.

As set forth above, an overdose of an AChEI may be administered to ahuman subject, in particular to a patient suffering from Alzheimer typedementia without concurrent cholinergic adverse effects by concomitantlyadministering an nsPAChA, at the aforementioned dose, to said subject orto said patient, the sole remaining adverse effect beingnausea/vomiting. This adverse effect may be alleviated by administrationof a non-anticholinergic antiemetic agent (naAEA).

Any antiemetic agent substantially devoid of central anticholinergiceffects may be used in order to block emesis due to the overdoses ofAChEIs which are administered according to the present invention. A listof typical naAEAs adapted to this use is reported in WO 2011/034568.Advantageous naAEAs are domperidone, at a daily dose of from 10 mg to 80mg, metoclopramide, at a daily dose of from 10 mg to 60 mg, aprepitant,at a dose of from 40 mg to 125 mg; alosetron, orally administered in0.5-mg or in 1-mg tablets at a dose of 0.5-1 mg, once or twice a day;dolasetron mesylate, orally administered in 50-mg or in 100-mg tablets,at a daily dose of 100 mg; granisetron, orally administered orally in1-mg or in 2-mg tablets, at a dose of 1 mg twice a day or 2 mg once aday, or parenterally administered in a 3-mg/1-ml solution for i.m.injection or in a 3 mg/3-ml solution for i.v. injection; ondansetron,orally administered in 4-mg or in 8-mg tablets at a dose of from 4 mg to24 mg; palonosetron, administered in a 0.25-mg/5-ml solution byintravenous injection at a dose of 0.25 mg; ramosetron, orally orintravenously administered at a dose of 5 mg; and tropisetron,administered either intravenously in a 2-mg/2-ml or 5-mg/5-ml solutionat a dose of 2 mg or 5 mg, or orally administered in a 5-mg capsule at adose of 5 mg; the above doses being referred to their contents in5-HT3-antagonist's base, unless otherwise specified.

C. The Fixed-Dose Combinations

As mentioned above, the nsPAChA may be formulated in a pharmaceuticalcomposition also containing an AChEI.

Thus, the present invention also provides a pharmaceutical unit formparticularly useful for inducing high and even very high bloodconcentrations of the AChEI in a human being, which comprises

-   -   (a) a nsPAChA selected from the group consisting of solifenacin,        pharmaceutically acceptable salts of solifenacin, propiverine,        pharmaceutically acceptable salts of propiverine, trospium        quaternary salts, clidinium quaternary salts, benzilonium        quaternary salts and glycopyrronium quaternary salts, in an        amount of from 100% to 800% the maximum amount contained in the        commercial products for the anticholinergic therapy; and        -   (b) an AChEI selected from the group consisting of            (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one            (donepezil) and pharmaceutically acceptable salts thereof,            (S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl            carbamate (rivastigmine) and pharmaceutically acceptable            salts thereof,            4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol            (galantamine) and pharmaceutically acceptable salts thereof,            and            (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0^(2,7)]trideca-2(7),3,10-trien-5-one            (huperzine A), in an amount of from 2.5 to 7 times the            maximum amount contained in the commercial products for the            treatment of Alzheimer type dementia.

Preferred Component (a) is a pharmaceutically acceptable salt oftrospium, especially trospium chloride, succinate, maleate, fumarate ortartrate, a pharmaceutically acceptable salt of solifenacin, especiallyits compound with succinic acid 1:1 (solifenacin succinate), apharmaceutically acceptable salt of propiverine, especially itshydrochloride, a pharmaceutical acceptable salt of glycopyrronium,especially glycopyrronium bromide; a pharmaceutically acceptable salt ofoxyphencyclimine, especially its hydrochloride or a pharmaceuticallyacceptable salt of tolterodine, especially its L-hydrogen tartrate.

Preferred Components (b) are donepezil hydrochloride, rivastigminehydrogen tartrate, galantamine hydrobromide; and huperzine A.

More particularly, the nsPAChA Component (a) is selected from the groupconsisting of trospium chloride, in an amount of from 20 mg to 480 mg,advantageously from 40 mg to 480 mg, preferably from 60 mg to 480 mg perdosage unit, solifenacin succinate, in an amount of from 10 mg to 80 mg,advantageously from 15 mg to 80 mg, preferably from 20 mg to 80 mg perdosage unit; and propiverine hydrochloride, in an amount of from 15 mgto 240 mg, advantageously from 20 mg to 240 mg, preferably from 30 mg to240 mg per dosage unit. A Component (a) selected from the groupconsisting of trospium chloride, in an amount of from 40 to 160 mg,preferably from 60 mg to 160 mg, in an IR formulation; propiverinehydrochloride, in an amount of from 15 mg to 120 mg, preferably from 30mg to 120 mg, in an IR formulation, trospium chloride, in an amount offrom 60 mg to 480 mg, preferably from 120 mg to 480 mg, in an ERformulation; glycopyrronium bromide, in an amount of from 4.1 to 16 mg,preferably from 4.5 to 12 mg in an IR formulation; and propiverinehydrochloride, in an amount of from 30 mg to 240 mg, preferably from 60mg to 240 mg, in an ER formulation; is particularly advantageous.

The AChEI Component (b) is selected from the group consisting ofdonepezil hydrochloride, in an amount of from 25 mg to 151 mg,preferably from 57.5 to 151 mg, per dosage unit; rivastigmine, as thehydrogen tartrate thereof, in an amount of from 15 mg to 126 mg,preferably from 24 mg to 126 mg per dose unit; galantamine, as thehydrobromide thereof, in an amount of from 40 to 224 mg per dose unit;and huperzine A, in an amount of from 150 μg to 1.2 mg, preferably from200 μg to 1.2 mg per dose unit. A Component (b) selected from the groupconsisting of rivastigmine (as hydrogen tartrate) in an IR oralformulation comprising from 15 mg to 42 mg of active ingredient;galantamine (as hydrobromide), in an IR formulation comprising from 40mg to 112 mg of active ingredient; rivastigmine (as hydrogen tartrate),in an ER patch formulation releasing from 45 mg/24 hours to 126 mg/24hours of active ingredient; and galantamine (as hydrobromide) in an ERformulation comprising from 60 mg to 168 mg of active ingredient; isparticularly advantageous.

The unit form of the present invention may be a tablet, a capsule, apre-measured volume of a liquid solution or suspension for oraladministration or a patch for transdermal application. In said unit formthe nsPAChA and the AChEI may be mixed together or separated accordingto known technologies in admixture with a pharmaceutical carrier in apharmaceutical composition.

Component (a) and Component (b) are formulated with conventionalpharmaceutical carriers in known formulations for oral use wherein saidcomponents are mixed together or separated, for example in two tabletsintroduced in a capsule or in a two-compartment capsule or in amultilayer (di-layer) tablet wherein the two components are both in IRor in ER form or one of the two components is in IR form and the otheris in ER form, according to known technologies.

The pharmaceutical carriers and vehicles are those commonly used for thepreparation of compositions for oral, buccal and parenteral, inparticular transdermal, administration. Appropriate unit forms comprisethe oral forms such as tablets, soft or hard gelatin capsules, powdersor granulates in sachets and suitably measured oral solutions orsuspensions as well as patches for transdermal administration.

Component (a) and component (b) may also be present in form of one oftheir complexes with a cyclodextrin, for example α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin ormethyl-β-cyclodextrin.

Component (a) and component (b) may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or additives.

For oral administration, Component (a) and Component (b), together orseparately, are formulated by mixing the active ingredient withconventional pharmaceutical acceptable carriers enabling said activeingredients to be formulated in tablets, dragees, orally disintegratingtablets, capsules, liquid solutions or suspensions, syrups and the like.

Carriers for IR tablets include for example starches, cellulose andderivatives thereof; lubricants such as talc, stearic acid or magnesiumstearate; diluents such as talc, powdered cellulose, lactose, starchessuch as maize or corn starch, mannitol, sorbitol; disaggregating agentssuch as microcrystalline cellulose or crospovidone; lubrifiants such aspolyethylenglycol or magnesium stearate; ligands such asmethylcellulose, sodium carboxymethylcellulose, alginic acid, alginates;sweeteners, such as saccharose, dextrose, mannitol, saccharin; orflavoring agents such as natural or synthetic oils.

Carriers for orally disintegrating tablets include for examplelubricants, aggregating, sweetening, flavoring or disaggregating agentsas well as agents improving the buccal mucosa absorption of components(a) and (b) such as sorbitol, mannitol, lactose and cellulose.

Carriers for liquid, normally aqueous, suspensions or solutions includefor example antioxidants, such as sodium metabisulfite or sodiumsulfite, thickening agents, such as microcrystalline cellulose,hydroxypropylcellulose, carboxymethylcellulose or polyvinylpyrrolidone,preservatives such as methyl paraben, ethyl paraben, sodiumethylenediaminotetracetate, sodium benzoate or an alkaline salt ofsorbic acid, as well as flavoring and sweetening agents.

The sweeteners contained in the orally disintegrating tablets and theliquid suspensions or solutions may be natural, optional reduced sugarssuch as sucrose, dextrose, xylitol, mannitol or sorbitol, or syntheticproduct such as sodium saccharine or aspartame.

The flavoring agents are pharmaceutically acceptable flavors and tastesof synthetic and natural oils, the latter extracted from plants, leaves,flowers, fruits and their combinations, such as cinnamon, peppermint,anise and citron leaves, bitter almond, citrus fruits, in particularorange and/or lemon, linden and grapefruit oils. Also chocolate, vanillaor eucalyptus flavor and essences of fruit, in particular apple, pear,peach, strawberry, cherry, apricot, orange, lemon and grapes may beadvantageously used.

The composition according to the present invention may be in form of acapsule containing two tablets as described herein above, one of themcomprising Component (a) and the other comprising Component (b).

The association nsPAChA/AChEI may be formulated in tablets in which oneor both of the two components is in controlled-release formulation, forexample as a dispersion of said component in hydroxypropyl methylcellulose or in a film-coated microgranule. Advantageously, the AChEI,in a ER-formulation is in the core and the nsPAChA, in IR-formulation,is in the outer layer in multi-layer tablets in which, for example, boththe core and the outer layer are coated with a film. Analogously,capsules made of two separated parts, one containing Component (a), inIR- or ER-formulation and the other containing Component (b), in IR- orER-formulation, may be used.

Carriers and vehicles for ER tablets include retardant materials such asis acrylic and methacrylic acid polymers and copolymers; cellulosederivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylethylcellulose, hydroxypropylcelluloses, methylcellulose,ethylcellulose, or sodium carboxymethylcellulose; gums; waxes;glycerides or aliphatic alcohols or a mixture thereof.

In particular, the unit forms of the present invention comprise a memberselected from the group consisting of trospium chloride, solifenacinsuccinate and propiverine hydrochloride, as an nsPAChA and a memberselected from the group consisting of donepezil hydrochloride, in anamount of from 25 mg to 151 mg; rivastigmine hydrogen tartrate; in anamount in rivastigmine of from 15 mg to 42 mg; galantamine hydrobromide,in an amount in galantamine of from 40 to 112 mg; and huperzine A, in anamount of from 150 μg to 1.2 mg as an AChEI.

According to an embodiment, the compositions of the present inventionare formulated by mixing the Component (a) and the Component (b)together, in admixture with a pharmaceutical carrier for an immediate orextended release and are useful for inducing increased AChEI plasmaconcentrations in a human subject or in a patient suffering from adementia of Alzheimer type treated with said AChEI.

An advantageous composition according to this embodiment comprises from20 mg to 160 mg preferably from 80 mg to 160 mg; of trospium chloride,as Component (a); and

-   -   from 15 mg to 42 mg, preferably form 18 mg to 42 mg, of        rivastigmine (as hydrogen tartrate); or    -   from 40 mg to 84 mg preferably from 42 mg to 84 mg, of        galantamine (as hydrobromide), as Component (b),        wherein Components (a) and (b) are mixed together and with a        pharmaceutical carrier in an IR formulation.

Another advantageous composition according to this embodiment comprises

-   -   from 10 mg to 80 mg, preferably from 20 mg to 80 mg, of        solifenacin succinate, as Component (a); and    -   from 25 mg to 70 mg, preferably from 40 mg to 70 mg, of        donepezil hydrochloride, as Component (b),        wherein Components (a) and (b) are mixed together and with a        pharmaceutical carrier in an IR formulation.

A particular composition according to this embodiment comprises

-   -   15 mg of solifenacin succinate, as Component (a); and    -   from 40 mg to 60 mg of donepezil hydrochloride, as Component        (b),        wherein Components (a) and (b) are mixed together and with a        pharmaceutical carrier in an IR formulation.

A further advantageous composition according to this embodimentcomprises

-   -   from 15 mg to 120 mg, preferably from 30 mg to 120 mg of        propiverine hydrochloride, as Component (a); and    -   from 15 mg to 42 mg, preferably form 18 mg to 42 mg, of        rivastigmine (as hydrogen tartrate); or    -   from 40 mg to 112 mg preferably from 42 mg to 112 mg, of        galantamine (as hydrobromide), as Component (b),        wherein Components (a) and (b) are mixed together and with a        pharmaceutical carrier in an IR formulation.

A particular composition according to this embodiment comprises

-   -   30 mg of propiverine hydrochloride, as Component (a); and    -   25 mg of rivastigmine (as hydrogen tartrate), as Component (b),        wherein Components (a) and (b) are mixed together and with a        pharmaceutical carrier in an IR formulation.

Another particular composition according to this embodiment comprises

-   -   45 mg of propiverine hydrochloride, as Component (a); and    -   60 mg of galantamine (as hydrobromide), as Component (b),        wherein Components (a) and (b) are mixed together and with a        pharmaceutical carrier in an ER formulation.

According to another embodiment, the compositions of the presentinvention are formulated by mixing the Component (a) with apharmaceutical carrier for an immediate or extended release in tablets(Tablet A) and the Component (b), separately, with a pharmaceuticalcarrier for an immediate or extended release in tablets (Tablet B) andintroducing Tablet A and Tablet B in a capsule for oral administrationas described for example in GB 1204580 or in US 2007/0224259. Anadvantageous composition according to this embodiment consists of softor hard gelatin capsules each containing

-   -   Tablet A comprising from 15 mg to 40 mg of propiverine        hydrochloride, as Component (a), in admixture with a        pharmaceutical carrier in a IR formulation; and    -   Tablet B, comprising from 25 mg to 35 mg of rivastigmine (as        hydrogen tartrate); as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

Another advantageous composition according to this embodiment consistsof soft or hard gelatin capsules each containing

-   -   Tablet A comprising from 2 mg to 16 mg of glycopyrrolium        bromide, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation; and    -   Tablet B, comprising from 25 mg to 42 mg of rivastigmine (as        hydrogen tartrate); as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A further advantageous composition according to this embodiment consistsof soft or hard gelatin capsules each containing

-   -   Tablet A comprising from 4 mg of glycopyrrolium bromide, as        Component (a), in admixture with a pharmaceutical carrier in a        IR formulation; and    -   Tablet B, 30 mg of rivastigmine (as hydrogen tartrate); as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

According to a further embodiment, the compositions according to thepresent invention are formulated in a di-layer tablet which releases twodrug doses, in which the release of a drug from one drug-containinglayer does not interfere with the release of a drug from the otherdrug-containing layer as described for example in WO 2006/089493. Anadvantageous composition according to this embodiment consists of

-   -   Layer A, comprising from 10 mg to 40 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation and    -   Layer B, comprising from 25 mg to 50 mg of donepezil        hydrochloride, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

According to another embodiment, the compositions of the presentinvention are formulated in patch for transdermal administration.Particularly advantageous compositions according to this embodiment aretransdermal patch formulations comprising

-   -   from 60 mg/24 hours to 480 mg/24 hours, preferably from 160        mg/24 hours to 480 mg/24 hours, of trospium chloride, as        Component (a); and    -   from 45 mg/24 hours to 126 mg/24 hours, preferably from 90 mg/24        hours to 126 mg/24 hours, of rivastigmine (as hydrogen        tartrate), as Component (b),        with a pharmaceutically acceptable carrier or diluent which is        suitable for systemic transdermal administration.

Another embodiment of the present invention provides unit formsconsisting of tablets comprising

-   -   from 10 mg to 15 mg, of solifenacin succinate, as Component (a);        and    -   from 25 mg to 50 mg preferably from 37.5 mg to 50 mg, of        donepezil hydrochloride;        as Component (b),        in admixture with a pharmaceutical carrier in a IR-formulation        for oral administration.

According to a preferred embodiment, the invention provides unit formsconsisting of tablets comprising

-   -   20 mg of solifenacin succinate, as Component (a) and    -   from 25 mg to 50 mg preferably from 37.5 mg to 50 mg, of        donepezil hydrochloride, as Component (b),        in admixture with a pharmaceutical carrier, in a formulation for        oral administration to be administered once a day.

Another preferred embodiment of the invention provides unit forms fororal administration consisting of tablets comprising

-   -   from 10 mg to 80 mg of solifenacin succinate, as Component (a)        and    -   from 25 mg to 151 mg preferably from 57.5 mg to 151 mg, of        donepezil hydrochloride, as Component (b),        in admixture with a pharmaceutical carrier, in formulation for        oral administration to be administered once a day.        IV. A Fourth Aspect of the Present Invention.

A fourth aspect of the present invention provides a pharmaceuticalcomposition comprising solifenacin or a pharmaceutically acceptable saltor compound thereof, and a naAEA, in admixture with a pharmaceuticalcarrier.

More particularly, it is an object of the present invention to provide acomposition comprising (a) (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (solifenacin) or apharmaceutically acceptable salt or compound thereof, in an amount whichis equivalent to from 10 mg to 80 mg of solifenacin succinate; and (b) anaAEA; in admixture with a pharmaceutical.

Solifenacin and pharmaceutically acceptable salts and compounds thereof,including the quaternary ammonium salts thereof, and their preparationare described in U.S. Pat. No. 6,017,927. Methods for the preparationand for the purification of solifenacin and its salts, in particular ofsolifenacin succinate, are described for example in WO 2007/076116, WO2009/139002, WO 2011/003624 and WO 2012/001481.

Advantageously, Component (a) of the composition is solifenacinsuccinate, in an amount of from 10 mg to 80 mg, advantageously from 11mg to 80 mg, more advantageously from to 15 mg to 80 mg, preferably from21 mg to 80 mg, most preferably from 21 mg to 40 mg.

The naAEA Component (b) is present in an amount of from 100% to 300% ofthe amount of the said naAEA contained as a sole active ingredient inthe currently used brand or generic drugs.

According to a preferred embodiment, said Component (b) is anon-anticholinergic antiemetic agent selected from the group consistingof (b1) 5HT3-antagonists, (b2) DA-antagonists, (b3) H1-antagonists, (b4)cannabinoids, (b5) aprepitant. Typical naAEAs of the above classes areillustrated in WO 2011/034568.

An advantageous Component (b) is selected from the group consisting ofalosetron and pharmaceutically acceptable salts and solvates thereof, inparticular the hydrochloride, in an amount (in alosetron) of from 0.5 mgto 3 mg; dolasetron and pharmaceutically acceptable salts and solvatesthereof, in particular the mesylate, in an amount (in dolasetron) offrom 50 mg to 300 mg; granisetron and pharmaceutically acceptable saltsand solvates thereof, in particular the hydrochloride, in an amount (ingranisetron) of from 1 mg to 3 mg; ondansetron and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloridedihydrate, in an amount (in ondansetron) of from 4 mg to 24 mg;tropisetron and pharmaceutically acceptable salts and solvates thereof,in particular the hydrochloride, in an amount of from 5 mg to 15 mg;domperidone and pharmaceutically acceptable salts and solvates thereof,in an amount (in domperidone) of from 10 mg to 30 mg; haloperidol, in anamount of from 1 mg to 30 mg; chlorpromazine and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in chlorpromazine) of from 25 mg to 75 mg;prochlorperazine and pharmaceutically acceptable salts and solvatesthereof, in particular the dimaleate, in an amount (in prochlorperazine)of from 5 mg to 30 mg; metoclopramide and pharmaceutically acceptablesalts and solvates thereof, in particular the monohydrochloridemonohydrate, in an amount (in metoclopramide) of from 10 mg to 30 mg;bromopride and pharmaceutically acceptable salts and solvates, inparticular the monohydrochloride and the dihydrochloride monohydrate, inan amount (in bromopride) of from 10 mg to 30 mg; clebopride andpharmaceutically acceptable salts and solvates thereof, in particularthe hydrogen malate and the hydrochloride monohydrate, in an amount (inclebopride) of from 0. 5 mg to 1.5 mg; levosulpiride, in an amount offrom 25 mg to 300 mg; alizapride and pharmaceutically acceptable saltsthereof, in particular the hydrochloride, in an amount (in alizapride)of from 50 mg to 150 mg; trimethobenzamide and pharmaceuticallyacceptable salts thereof such as the monohydrochloride, in an amount (intrimethobenzamide) of from 300 mg to 900 mg; meclizine andpharmaceutically acceptable salts and solvates thereof, in an amount (inmeclizine) of from 13 mg to 150 mg; promethazine and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in prometazine) of from 25 mg to 150 mg; dronabinol in anamount of from 2.5 mg to 60 mg; nabilone, in an amount of from 2 mg to12 mg; and aprepitant, in an amount of from 40 mg to 375 mg.

An advantageous non-anticholinergic antiemetic agent Component (b) insaid pharmaceutical composition is selected from the group consisting ofalosetron and pharmaceutically acceptable salts and solvates thereof, inan amount (in alosetron) of from 0. 5 mg to 3 mg; dolasetron andpharmaceutically acceptable salts thereof, in an amount (in dolasetron)of from 50 mg to 300 mg; granisetron and pharmaceutically acceptablesalts thereof, in an amount (in granisetron) of from 1 mg to 3 mg;ondansetron and pharmaceutically acceptable salts and solvates thereof,in an amount (in ondansetron) of from 4 mg to 24 mg; tropisetron andpharmaceutically acceptable salts thereof, in an amount (in tropisetron)of from 5 mg to 15 mg; domperidone and pharmaceutically acceptable saltsand solvates thereof, in an amount (in domperidone) of from 10 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in an amount (in metoclopramide) of from 10 mg to 30 mg;bromopride and pharmaceutically acceptable salts and solvates thereof,in an amount (in bromopride) of from 10 mg to 30 mg; clebopride andpharmaceutically acceptable salts thereof, in an amount (in clebopride)of from 0.5 mg to 1.5 mg; and aprepitant, in an amount of from 40 mg to375 mg.

Preferred Component (b) is a naAEA selected from the group consisting ofalosetron and pharmaceutically acceptable salts and solvates thereof, inan amount (in alosetron) of from 0. 5 mg to 3 mg; granisetron andpharmaceutically acceptable salts and solvates thereof, in particularthe hydrochloride, in an amount (in granisetron) of from 1 mg to 3 mg;ondansetron and pharmaceutically acceptable salts and solvates thereof,in an amount (in ondansetron) of from 4 mg to 24 mg; tropisetron andpharmaceutically acceptable salts thereof, in an amount (in tropisetron)of from 5 mg to 15 mg; domperidone and pharmaceutically acceptable saltsand solvates thereof, in an amount (in domperidone) of from 10 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in an amount (in metoclopramide) of from 10 mg to 30 mg.

A composition comprising (a) solifenacin succinate in an amount of from10 mg to 80 mg, advantageously from 11 mg to 80 mg, more advantageouslyfrom to 15 mg to 80 mg, preferably from 21 mg to 80 mg, most preferablyfrom 21 mg to 40 mg; and (b); and a naAEA selected from the groupconsisting of granisetron hydrochloride in an amount (in granisetron) offrom 1 mg to 3 mg, ondansetron hydrochloride dihydrate in an amount (inondansetron) of from 4 mg to 24 mg, domperidone in an amount of from 10mg to 30 mg; and metoclopramide monohydrochloride monohydrate in anamount (in metoclopramide) of from 10 mg to 30 mg; and aprepitant, in anamount of from 40 mg to 375 mg, in admixture with a pharmaceuticalcarrier, is an advantageous embodiment of the present invention; thesame composition, wherein Component (a) is solifenacin succinate in anamount of from 10 mg to 30 mg, from 15 mg to 30 mg or from 21 mg to 30mg being particularly preferred.

The pharmaceutical compositions of the present invention are formulatedin unit form for oral use, preferably in an immediate releaseformulation.

The unit form of the present invention may be a tablet, a capsule, or apre-measured amount of granulate for oral administration comprisingComponent (a) and Component (b) in admixture with a pharmaceuticalcarrier. In said unit form solifenacin and the naAEA may be mixedtogether or separated according to known technologies in admixture witha pharmaceutical carrier in a pharmaceutical composition.

Component (a) and Component (b) are formulated with conventionalpharmaceutical carriers in known formulations for oral use wherein saidcomponents are mixed together or separated, for example in two tabletsintroduced in a capsule or in a two-compartment capsule or in amultilayer (di-layer) tablet wherein the two components are both in IRform, even though in one of the layers, Component (a) is in IR form andComponent (b) may be in ER form, according to known technologies.

The pharmaceutical carriers and vehicles are those commonly used for thepreparation of compositions for oral, buccal and parenteral, inparticular transdermal, administration. Appropriate unit forms comprisethe oral forms such as tablets, soft or hard gelatin capsules, powdersor granulates in sachets and suitably measured oral solutions orsuspensions as well as patches for transdermal administration.

Component (a) and Component (b) may also be present in form of one oftheir complexes with a cyclodextrin, for example α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin ormethyl-β-cyclodextrin.

Component (a) and Component (b) may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or additives.

For oral administration, Component (a) and Component (b), together orseparately, are formulated by mixing the active ingredient withconventional pharmaceutical acceptable carriers enabling said activeingredients to be formulated in tablets, dragees, orally disintegratingtablets, capsules and the like.

Carriers for IR tablets include for example starches, cellulose andderivatives thereof; lubricants such as talc, stearic acid or magnesiumstearate; diluents such as talc, powdered cellulose, lactose, starchessuch as maize or corn starch, mannitol, sorbitol; disaggregating agentssuch as microcrystalline cellulose or crospovidone; lubrifiants such aspolyethylenglycol or magnesium stearate; ligands such asmethylcellulose, sodium carboxymethylcellulose, alginic acid, alginates;sweeteners, such as saccharose, dextrose, mannitol, saccharin; orflavoring agents such as natural or synthetic oils.

Carriers for orally disintegrating tablets include for examplelubricants, aggregating, sweetening, flavoring or disaggregating agentsas well as agents improving the buccal mucosa absorption of components(a) and (b) such as sorbitol, mannitol, lactose and cellulose.

The sweeteners contained in the orally disintegrating tablets may benatural, optional reduced sugars such as sucrose, dextrose, xylitol,mannitol or sorbitol, or synthetic product such as sodium saccharine oraspartame.

The flavoring agents are pharmaceutically acceptable flavors and tastesof synthetic and natural oils, the latter extracted from plants, leaves,flowers, fruits and their combinations, such as cinnamon, peppermint,anise and citron leaves, bitter almond, citrus fruits, in particularorange and/or lemon, linden and grapefruit oils. Also chocolate, vanillaor eucalyptus flavor and essences of fruit, in particular apple, pear,peach, strawberry, cherry, apricot, orange, lemon and grapes may beadvantageously used.

The composition according to the present invention may be in form of acapsule containing two tablets as described herein above, one of themcomprising Component (a) and the other comprising Component (b).

The association solifenacin/naAEA may be formulated in tablets in whichone or both of the two components is in controlled-release formulation,for example as a dispersion of said component in hydroxypropyl methylcellulose or in a film-coated microgranule. In this case the naAEA, inan ER-formulation, is in the core and the nsPAChA, in IR-formulation, isin the outer layer in multi-layer tablets in which, for example, boththe core and the outer layer are coated with a film. Analogously,capsules made of two separated parts, one containing Component (a), inIR-formulation and the other containing Component (b), in IR- orER-formulation, may be used.

Advantageous ER administration formulations are in form of a transdermalpatch manufactured according to known technologies, for administeringthe solifenacin/antiemetic composition continuously and transdermallythrough a selected area of intact skin in a controlled manner for aprolonged period of time to induce high AChEI blood levels in a humansubject, in particular to a patient suffering from a dementia ofAlzheimer type, said subject or patient being treated with said AChEI.Said high AChEI blood levels enable AChEI concentrations in the brain torise sufficiently to afford neuroprotection.

Carriers and vehicles for ER formulations include retardant materialssuch as acrylic and methacrylic acid polymers and copolymers; cellulosederivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylethylcellulose, hydroxypropylcelluloses, methylcellulose,ethylcellulose, or sodium carboxymethylcellulose; gums; waxes;glycerides or aliphatic alcohols or a mixture thereof.

In particular, the unit forms of the present invention comprisesolifenacin succinate, in an amount of from 10 to 80 mg and a memberselected from the group consisting of domperidone, in an amount of from10 mg to 30 mg; metoclopramide monohydrochloride monohydrate, in anamount (in metoclopramide) of from 10 mg to 30 mg; alosetronhydrochloride, in an amount, in alosetron of from 0.5-mg to 3 mg),dolasetron mesylate, in an amount of from 50 mg to 300 mg; granisetronhydrochloride in an amount, in granisetron, of from 1 mg to 3 mg;ondansetron hydrochloride monohydrate in an amount, in ondansetron, offrom 4 to 24 mg; tropisetron hydrochloride in an amount, in tropisetron,of from 5 mg to 15 mg; and aprepitant, in an amount of from 40 mg to 375mg.

According to an embodiment, the compositions of the present inventionare formulated by mixing solifenacin succinate, as Component (a), andthe naAEA, as Component (b), together with a pharmaceutical carrier andcompressed to a tablet for an immediate release or introduced in a softor hard capsule for an immediate release.

An advantageous solifenacin/granisetron composition according to thisembodiment comprises

-   -   from 10 mg to 80 mg of solifenacin succinate, as Component (a);        and    -   from 1 mg to 3 mg of granisetron (as hydrochloride);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous solifenacin/granisetron compositioncomprises

-   -   10 mg of solifenacin succinate, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous solifenacin/granisetron compositionaccording to this embodiment comprises

-   -   15 mg of solifenacin succinate, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous solifenacin/granisetron composition according tothis embodiment comprises

-   -   21 mg of solifenacin succinate, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous solifenacin/granisetron composition according tothis embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   1 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous solifenacin/granisetron composition according tothis embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   2 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A sixth advantageous solifenacin/granisetron composition according tothis embodiment comprises

-   -   40 mg of solifenacin succinate, as Component (a); and    -   2 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A seventh advantageous solifenacin/granisetron composition according tothis embodiment comprises

-   -   80 mg of solifenacin succinate, as Component (a); and    -   3 mg of granisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous solifenacin/ondansetron composition according to thisembodiment comprises

-   -   from 10 mg to 80 mg of solifenacin succinate, as Component (a);        and    -   from 4 mg to 24 mg of ondansetron (as hydrochloride dihydrate);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous solifenacin/ondansetron compositionaccording to this embodiment comprises

-   -   10 mg of solifenacin succinate, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous solifenacin/ondansetron compositionaccording to this embodiment comprises

-   -   15 mg of solifenacin succinate, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous solifenacin/ondansetron composition according tothis embodiment comprises

-   -   21 mg of solifenacin succinate, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous solifenacin/ondansetron composition according tothis embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   4 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous solifenacin/ondansetron composition according tothis embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   8 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A sixth advantageous solifenacin/ondansetron composition according tothis embodiment comprises

-   -   40 mg of solifenacin succinate, as Component (a); and    -   8 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A seventh advantageous solifenacin/ondansetron composition according tothis embodiment comprises

-   -   80 mg of solifenacin succinate, as Component (a); and    -   20 mg of ondansetron (as hydrochloride dihydrate), as Component        (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous solifenacin/tropisetron composition according to thisembodiment comprises

-   -   from 10 mg to 80 mg of solifenacin succinate, as Component (a);        and    -   from 5 mg to 15 mg of tropisetron (as hydrochloride), as        Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous solifenacin/tropisetron compositionaccording to this embodiment comprises

-   -   10 mg of solifenacin succinate, as Component (a); and    -   5 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous solifenacin/tropisetron compositionaccording to this embodiment comprises

-   -   15 mg of solifenacin succinate, as Component (a); and    -   5 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous solifenacin/tropisetron composition according tothis embodiment comprises

-   -   21 mg of solifenacin succinate, as Component (a); and    -   5 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous solifenacin/tropisetron composition according tothis embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   5 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous solifenacin/tropisetron composition according tothis embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   10 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A sixth advantageous solifenacin/tropisetron composition according tothis embodiment comprises

-   -   40 mg of solifenacin succinate, as Component (a); and    -   10 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A seventh advantageous solifenacin/tropisetron composition according tothis embodiment comprises

-   -   80 mg of solifenacin succinate, as Component (a); and    -   15 mg of tropisetron (as hydrochloride), as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous solifenacin/dolasetron composition according to thisembodiment comprises

-   -   from 10 mg to 80 mg of solifenacin succinate, as Component (a);        and    -   from 50 mg to 300 mg of dolasetron (as mesylate), as Component        (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A particular advantageous solifenacin/dolasetron composition accordingto this embodiment comprises

-   -   15 mg, 17.5 mg or 21 mg of solifenacin succinate, as Component        (a); and    -   50 mg of dolasetron (as mesylate), as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous solifenacin/alosetron composition according to thisembodiment comprises

-   -   from 10 mg to 80 mg of solifenacin succinate, as Component (a);        and    -   from 0.5 mg to 3 mg of alosetron (as mesylate), as Component        (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A particular advantageous solifenacin/alosetron composition according tothis embodiment comprises

-   -   15 mg, 17.5 mg or 21 mg of solifenacin succinate, as Component        (a); and    -   2 mg of alosetron (as mesylate), as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous solifenacin/domperidone composition according to thisembodiment comprises

-   -   from 10 mg to 80 mg of solifenacin succinate, as Component (a);        and    -   from 10 mg to 30 mg of domperidone, as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous solifenacin/domperidone compositionaccording to this embodiment comprises

-   -   10 mg of solifenacin succinate, as Component (a); and    -   10 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous solifenacin/domperidone compositionaccording to this embodiment comprises

-   -   15 mg of solifenacin succinate, as Component (a); and    -   10 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous solifenacin/domperidone composition according tothis embodiment comprises

-   -   21 mg of solifenacin succinate, as Component (a); and    -   10 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous solifenacin/domperidone composition according tothis embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   10 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous solifenacin/domperidone composition according tothis embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   20 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A sixth advantageous solifenacin/domperidone composition according tothis embodiment comprises

-   -   40 mg of solifenacin succinate, as Component (a); and    -   20 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A seventh advantageous solifenacin/domperidone composition according tothis embodiment comprises

-   -   80 mg of solifenacin succinate, as Component (a); and    -   30 mg of domperidone, as Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

An advantageous solifenacin/metoclopramide composition according to thisembodiment comprises

-   -   from 10 mg to 80 mg of solifenacin succinate, as Component (a);        and    -   from 10 mg to 30 mg of metoclopramide, as Component (b);        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A first particularly advantageous composition according to thisembodiment comprises

-   -   10 mg of solifenacin succinate, as Component (a); and    -   10 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A second particularly advantageous composition according to thisembodiment comprises

-   -   15 mg of solifenacin succinate, as Component (a); and    -   10 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A third advantageous composition according to this embodiment comprises

-   -   21 mg of solifenacin succinate, as Component (a); and    -   10 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fourth advantageous composition according to this embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   10 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A fifth advantageous composition according to this embodiment comprises

-   -   25 mg of solifenacin succinate, as Component (a); and    -   20 mg of domperidone, as Component (b),

A sixth advantageous composition according to this embodiment comprises

-   -   40 mg of solifenacin succinate, as Component (a); and    -   20 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

A seventh advantageous composition according to this embodimentcomprises

-   -   80 mg of solifenacin succinate, as Component (a); and    -   30 mg of metoclopramide (as monohydrochloride monohydrate), as        Component (b),        as mixed together and with a pharmaceutical carrier in an IR        formulation.

According to a second embodiment, the compositions of the presentinvention are formulated by mixing solifenacin succinate, as theComponent (a) with a pharmaceutical carrier for an immediate or extendedrelease in tablets (Tablet A) and the naAEA Component (b), separately,with a pharmaceutical carrier for an immediate or extended release intablets (Tablet B) and introducing Tablet A and Tablet B in a capsulefor oral administration as described for example in GB 1204580 or in US2007/0224259, thus obtaining a unit form to be administered to a patientsuffering from a dementia of Alzheimer type.

An advantageous solifenacin/granisetron unit form according to thisembodiment consists of preferably hard gelatin capsules each containing

-   -   Tablet A comprising from 10 mg to 80 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation; and    -   Tablet B, comprising from 1 to 3 mg of granisetron (as        hydrochloride), as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A first particularly advantageous solifenacin/granisetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation; and    -   Tablet B, comprising 1 mg of granisetron (as hydrochloride), as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A second particularly advantageous solifenacin/granisetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation; and    -   Tablet B, comprising 2 mg of granisetron (as hydrochloride), as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A third advantageous solifenacin/granisetron unit form according to thisembodiment contains

-   -   Tablet A comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation; and    -   Tablet B, comprising 3 mg of granisetron (as hydrochloride), as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

An advantageous solifenacin/ondansetron unit form according to thisembodiment consists of preferably hard gelatin capsules each containing

-   -   Tablet A comprising from 10 mg to 80 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation; and    -   Tablet B, comprising from 4 to 24 mg of ondansetron (as        hydrochloride dihydrate), as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A first particularly advantageous solifenacin/ondansetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation; and    -   Tablet B, comprising 4 mg of granisetron (as hydrochloride        dihydrate), as Component (b), in admixture with a pharmaceutical        carrier in an IR-formulation.

A second particularly advantageous solifenacin/ondansetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation; and    -   Tablet B, comprising 8 mg of ondansetron (as hydrochloride        dihydrate), as Component (b), in admixture with a pharmaceutical        carrier in an IR-formulation.

A third advantageous solifenacin/ondansetron unit form according to thisembodiment contains

-   -   Tablet A comprising 15 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation; and    -   Tablet B, comprising 8 mg of ondansetron (as hydrochloride        dihydrate), as Component (b), in admixture with a pharmaceutical        carrier in an IR-formulation.

An advantageous solifenacin/tropisetron unit form according to thisembodiment consists of preferably hard gelatin capsules each containing

-   -   Tablet A comprising from 10 mg to 80 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation; and    -   Tablet B, comprising from 5 to 15 mg of tropisetron as Component        (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A first particularly advantageous solifenacin/granisetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation; and    -   Tablet B, comprising 5 mg of tropisetron (as hydrochloride), as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A second particularly advantageous solifenacin/tropisetron unit formaccording to this embodiment contains

-   -   Tablet A comprising 15 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation; and    -   Tablet B, comprising 5 mg of tropisetron (as hydrochloride), as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

An advantageous solifenacin/domperidone unit form according to thisembodiment consists of preferably hard gelatin capsules each containing

-   -   Tablet A comprising from 10 mg to 80 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation; and    -   Tablet B, comprising from 10 to 30 mg of domperidone as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A particularly advantageous solifenacin/domperidone unit form accordingto this embodiment contains

-   -   Tablet A comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation; and    -   Tablet B, comprising 10 mg of domperidone as Component (b), in        admixture with a pharmaceutical carrier in an IR-formulation.

An advantageous solifenacin/metoclopramide unit form according to thisembodiment consists of preferably hard gelatin capsules each containing

-   -   Tablet A comprising from 10 mg to 80 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation; and    -   Tablet B, comprising from 10 to 30 mg of metoclopramide (as        monohydrochloride monohydrate) as Component (b), in admixture        with a pharmaceutical carrier in an IR-formulation.

A particularly advantageous solifenacin/metoclopramide unit formaccording to this embodiment contains

-   -   Tablet A comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation; and    -   Tablet B, comprising 10 mg of metoclopramide (as        monohydrochloride monohydrate) as Component (b), in admixture        with a pharmaceutical carrier in an IR-formulation.

According to a third embodiment, the compositions according to thepresent invention are formulated in a di-layer tablet, one comprisingfrom 10 mg to 80 mg of solifenacin succinate and the other comprising anaAEA, which releases the two drug doses, in which the release of a drugfrom one drug-containing layer does not interfere with the release of adrug from the other drug-containing layer as described for example in WO2006/089493.

An advantageous solifenacin/granisetron composition according to thisembodiment consists of

-   -   Layer A, comprising from 10 mg to 80 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation and    -   Layer B, comprising from 1 to 3 mg of granisetron, as        hydrochloride, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A first particularly advantageous solifenacin/granisetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation and    -   Layer B, comprising 1 mg of granisetron, as hydrochloride, as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A second particularly advantageous solifenacin/granisetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation and    -   Layer B, comprising 2 mg of granisetron, as hydrochloride, as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A third particularly advantageous solifenacin/granisetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation and    -   Layer B, comprising 2 mg of granisetron, as hydrochloride, as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

An advantageous solifenacin/ondansetron composition according to thisembodiment consists of

-   -   Layer A, comprising from 10 mg to 80 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation and    -   Layer B, comprising from 4 to 24 mg of ondansetron, as        hydrochloride dihydrate, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A first particularly advantageous solifenacin/ondansetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation and    -   Layer B, comprising 4 mg of ondansetron, as hydrochloride        dihydrate, as Component (b), in admixture with a pharmaceutical        carrier in an IR-formulation.

A second particularly advantageous solifenacin/ondansetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation and    -   Layer B, comprising 8 mg of ondansetron, as hydrochloride        dihydrate, as Component (b), in admixture with a pharmaceutical        carrier in an IR-formulation.

An advantageous solifenacin/tropisetron composition according to thisembodiment consists of

-   -   Layer A, comprising from 10 mg to 80 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation and    -   Layer B, comprising from 5 to 15 mg of tropisetron, as        hydrochloride, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A particularly advantageous solifenacin/tropisetron compositionaccording to this embodiment consist of

-   -   Layer A, comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation and    -   Layer B, comprising 5 mg of tropisetron, as hydrochloride, as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

An advantageous solifenacin/domperidone composition according to thisembodiment consists of

-   -   Layer A, comprising from 10 mg to 80 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation and    -   Layer B, comprising from 10 to 30 mg of domperidone, as        Component (b), in admixture with a pharmaceutical carrier in an        IR-formulation.

A particularly advantageous solifenacin/domperidone compositionaccording to this embodiment consist of

-   -   Layer A, comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation and    -   Layer B, comprising 10 mg of domperidone, as Component (b), in        admixture with a pharmaceutical carrier in an IR-formulation.

An advantageous solifenacin/metoclopramide composition according to thisembodiment consists of

-   -   Layer A, comprising from 10 mg to 80 mg of solifenacin        succinate, as Component (a), in admixture with a pharmaceutical        carrier in a IR formulation and    -   Layer B, comprising from 10 to 30 mg of metoclopramide, as        monohydrochloride hydrate, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

A particularly advantageous solifenacin/metoclopramide compositionaccording to this embodiment consist of

-   -   Layer A, comprising 10 mg of solifenacin succinate, as Component        (a), in admixture with a pharmaceutical carrier in a IR        formulation and    -   Layer B, comprising 10 mg of metoclopramide, as        monohydrochloride hydrate, as Component (b), in admixture with a        pharmaceutical carrier in an IR-formulation.

Another embodiment of the present invention provides unit formsconsisting of tablets comprising

-   -   from 10 mg to 15 mg, of solifenacin succinate, as Component (a);        and    -   from 25 mg to 50 mg preferably from 37.5 mg to 50 mg, of        donepezil hydrochloride;        as Component (b),        in admixture with a pharmaceutical carrier in a IR-formulation        for oral administration.

The above combined pharmaceutical compositions are able to assuregreater and longer efficacy and less adverse effects of co-administeredAChEIs by allowing the safe and tolerable administration of larger andthus more therapeutically effective quantities (from 2.5 to 7 times themaximum recommended doses) of said AChEIs in human subjects treated withsaid AChEI. In particular, by inducing very high blood levels in humansubjects, the above combined compositions assure an increasedconcentration of AChEIs to the CNS of patients suffering from a dementiaof Alzheimer type which are treated even with very high doses of AChEI.

In particular, the compositions of the present invention are safe andeffective, for the treatment of patients in need of an AChEI, inparticular of patients suffering from dementias of the Alzheimer type,concurrently or sequentially treated with an AChEI, on a once dailybasis.

The pathologic conditions treated with the composition of the presentinvention include, but are not limited to, Alzheimer's disease,Parkinson's disease dementia, and other chronic disorders of humancognitive and neurobehavioral function that are treated, in part, bypharmaceuticals intended to augment brain acetylcholine-mediatedneurotransmission.

The therapeutic efficacy is measured by the degree to which cognitiveand other neurobehavioral disabilities associated with dementias of theAlzheimer type, as documented by the use of standard scales, arereduced.

Thus, the present invention also provides a method for inducingneuroprotection, thus combating neurodegeneration, and consequentlyslowing disease progression in a patient suffering from a dementia ofthe Alzheimer type, which comprises administering to said patient anAChEI daily dose which is at least 2.5, up to 7 times the maximumrecommended daily dose of said AChEI used in the treatment of Alzheimertype dementias, in combination with a pharmaceutical compositioncomprising an nsPAChA selected from the group consisting of(1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate and pharmaceuticallyacceptable salts and compounds thereof, in an amount which is equivalentto from 10 mg to 80 mg, advantageously from 11 mg to 80 mg, preferablyfrom 21 mg to 80 mg, of solifenacin succinate; and (b) anon-anticholinergic antiemetic agent (naAEA); in admixture with apharmaceutical carrier. Said pharmaceutical composition is exhaustivelyillustrated herein above.

EXAMPLES

The following examples illustrate various aspects of the invention.

Synthesis of a Propiverinium Alkyl Halide

Propiverine hydrochloride (50 mg, 0.12 mM) is suspended in water (10ml). 2M aqueous sodium carbonate (0.5 ml, 1.0 mM) is added and thereaction mixture is extracted twice with ethyl acetate. The organicphase is dried over anhydrous sodium sulfate and concentrated underreduce pressure. The residue is dissolved in dry ethanol (5 ml) and theethanolic solution is cooled to 0° C. Methyl iodide (25 ml, 0.40 mM) isthen added and the reaction mixture is stirred at room temperature for18 hours (formation of a white solid). The solid formed is filtered off,washed with small amounts of ethanol and dried under vacuum to afford1,1-dimethyl-4-[(2,2-diphenyl-2-propoxy)acetoxy]piperidinium iodide(methylpropiverinium iodide) as a white solid (30 mg; yield: 48%).Melting point: 248° C.-250° C.

[C₂₄H₃₂NO₃]⁺382.4 (m/z). ¹H NMR 300 MHz (DMSO D₆), d: 0.84 (t, 3H, j=7.5Hz), 1.50 (qui, 2H, j1=7.5 Hz, j2=6.6 Hz), 1.82 (br. s., 2H), 2.06 (br.s., 2H), 2.91 (br. t., 2H, j=9.3 Hz), 2.94 (s, 3H), 3.02 (s, 3H), 3.14(t, 2H, j=6.6 Hz), 3.35 (br. s., 2H), 5.00 (m, 1H), 7.37 (m, 10H).

Example 1 Synthesis of a Propiverinium Alkyl Halide

Propiverine hydrochloride (50 mg, 0.12 mM) is suspended in water (10ml). 2M aqueous sodium carbonate (0.5 ml, 1.0 mM) is added and thereaction mixture is extracted twice with ethyl acetate. The organicphase is dried over anhydrous sodium sulfate and concentrated underreduce pressure. The residue is dissolved in dry ethanol (5 ml) and theobtained solution is cooled to 0° C. Methyl iodide (25 ml, 0.40 mM) isthen added and the reaction mixture is stirred at room temperature for18 hours (formation of a white solid). The solid formed is filtered off,washed with small amounts of ethanol and dried under vacuum to afford1,1-dimethyl-4-[(2,2-diphenyl-2-propoxy)acetoxy]piperidinium iodide(methylpropiverinium iodide) as a white solid (30 mg; yield: 48%).Melting point: 248° C.-250° C.

[C₂₄H₃₂NO₃]⁺382.4 (m/z). ¹H NMR 300 MHz (DMSO D₆), d: 0.84 (t, 3H, j=7.5Hz), 1.50 (qui, 2H, j1=7.5 Hz, j2=6.6 Hz), 1.82 (br. s., 2H), 2.06 (br.s., 2H), 2.91 (br. t., 2H, j=9.3 Hz), 2.94 (s, 3H), 3.02 (s, 3H), 3.14(t, 2H, j=6.6 Hz), 3.35 (br. s., 2H), 5.00 (m, 1H), 7.37 (m, 10H).

By operating as described above, by using 0.40 mM of methyl bromideinstead of the same amount of methyl iodide,1,1-dimethyl-4-[(2,2-diphenyl-2-propoxy)acetoxy]piperidinium bromide(methylpropiverinium bromide) is obtained.

Example 2

In one embodiment, the capsules for oral administration are prepared bymixing the following ingredients:

Ingredients Parts by weight Propiverine hydrochloride 2,000 Ondansetronhydrochloride dihydrate 1,000 Lactose USP 7,500 Colloidal silicondioxide (Aerosil ®) 50

After mixing, the mixture is screened through a 40 mesh screen andintroduced in two-piece hard gelatin capsule No. 3 containing 8 mg ofondansetron (as hydrochloride dihydrate) and 20 mg of propiverinehydrochloride. Similarly, capsules containing 15 mg or 25 mg ofpropiverine hydrochloride and 8 mg of ondansetron (as hydrochloridedihydrate) are prepared.

In another embodiment, the capsules for oral administration are preparedby mixing the following ingredients:

Ingredients Parts by weight Donepezil hydrochloride 5,000 Solifenacinsuccinate 2,100 Mannitol 7,350 Colloidal silicon dioxide (Aerosil ®) 50

After mixing, the mixture is screened through a 40 mesh screen andintroduced in two-piece hard gelatin capsule No. 1 containing 50 mg ofdonepezil hydrochloride and 21 mg of solifenacin succinate. Similarly,capsules containing 25 mg of solifenacin succinate and 50 mg ofdonepezil hydrochloride are prepared.

In yet another embodiment, the capsules for oral administration areprepared by mixing the following ingredients:

Ingredients Parts by weight Donepezil hydrochloride 4,000 Solifenacinsuccinate 1,000 Mannitol 7,350 Colloidal silicon dioxide (Aerosil ®) 50

After mixing, the mixture is screened through a 40 mesh screen andintroduced in two-piece hard gelatin capsule No. 2 containing 40 mg ofdonepezil hydrochloride and 10 mg of solifenacin succinate. Similarly,capsules containing 15 mg or 20 mg of solifenacin succinate and 40 mg ofdonepezil hydrochloride are prepared.

In yet another embodiment, the capsules for oral administration areprepared by mixing the following ingredients:

Ingredients Parts by weight Solifenacin succinate 2,000 Ondansetronhydrochloride dihydrate 1,000 Lactose USP 7,350 Colloidal silicondioxide (Aerosil ®) 50

After mixing, the mixture is screened through a 40 mesh screen andintroduced in two-piece hard gelatin capsule No. 3 containing 8 mg ofondansetron (as hydrochloride dihydrate) and 20 mg of solifenacinsuccinate. Similarly, capsules containing 10 mg or 15 mg of solifenacinsuccinate and 8 mg of ondansetron (as hydrochloride dihydrate areprepared).

Example 3

According to one embodiment, immediate release tablets for oraladministration are prepared by mixing 1.5 kg of propiverinehydrochloride and 5.0 kg of dolasetron mesylate, 0.3 kg of gelatin, 0.3kg of magnesium stearate and 10 kg of corn starch and forming themixture into tablets containing 15 mg of propiverine hydrochloride and50 mg of dolasetron mesylate by a conventional tableting machine.Similarly, tablets containing 17.5 mg or 20 mg of propiverinehydrochloride and 50 mg of dolasetron mesylate are prepared.

According to another embodiment, immediate release tablets for oraladministration are prepared by mixing 2.5 kg of solifenacin succinateand 6 kg of donepezil hydrochloride, 0.3 kg of gelatin, 0.3 kg ofmagnesium stearate and 12 kg of corn starch and forming the mixture intotablets containing 25 mg of solifenacin succinate and 60 mg of donepezilhydrochloride by a conventional tableting machine. Similarly, tabletscontaining 30 mg of solifenacin succinate and 60 mg of donepezilhydrochloride are prepared.

In yet another embodiment, immediate release tablets for oraladministration are prepared by mixing 1.5 kg of solifenacin succinateand 5.0 kg of donepezil hydrochloride, 0.3 kg of gelatin, 0.3 kg ofmagnesium stearate and 10 kg of corn starch and forming the mixture intotablets containing 15 mg of solifenacin succinate and 50 mg of donepezilhydrochloride by a conventional tableting machine. Similarly, tabletscontaining 17.5 mg or 20 mg of solifenacin succinate and 40 mg ofdonepezil hydrochloride are prepared.

In yet another embodiment, immediate release tablets for oraladministration are prepared by mixing 1.5 kg of solifenacin succinateand 5.0 kg of dolasetron mesylate, 0.3 kg of gelatin, 0.3 kg ofmagnesium stearate and 10 kg of corn starch and forming the mixture intotablets containing 15 mg of solifenacin succinate and 50 mg ofdolasetron mesylate by a conventional tableting machine. Similarly,tablets containing 17.5 mg or 10 mg of solifenacin succinate and 50 mgof dolasetron mesylate are prepared.

Example 4

Tablets for IR oral administration containing 2 mg of glycopyrroniumbromide formulated with a pharmaceutical carrier and tablets containing10 mg of metoclopramide (as monohydrochloride monohydrate) formulatedwith a pharmaceutical carrier are distributed in capsules as describedin GB 1,204,580, such that unit dosage forms containing 2 mg ofglycopyrronium bromide and 10 mg of metoclopramide (as monohydrochloridemonohydrate) are prepared.

Example 5 Maximum Tolerated Dose and Plasma Levels of RivastigmineIncrease Enabled by Co-Administered Trospium

In this single-blind crossover study, healthy volunteers werehospitalized at a Phase I Center (Forenap, Rouffach, France) for theonce daily oral administration of ascending doses of rivastigminehydrogen tartrate (“rivastigmine”), (3 mg to a possible maximum of 24 mgin 3 mg increments as tolerated) together with placebo trospium and thenwith ascending amounts of rivastigmine (3 mg to a possible maximum of 24mg as tolerated) together with active trospium. Placebo trospium oractive trospium (at a fixed dose of 40 mg per day) were given orallyonce daily 3 hours before rivastigmine administration. Venous blood wascollected for the measurement of plasma drug levels at their nominalpeaks (approximately 1 hour after rivastigmine administration). Subjectswere monitored clinically for 4 hours after drug administration or untilall adverse events had subsided. Safety and tolerability were evaluatedbased on subject reports, physician observations and examinations, andthe performance of standard laboratory tests.

Subject (a) Age 43 years, weight 84 kg. The subject tolerated a dose of9 mg of rivastigmine when given with placebo trospium and of 24 mg whengiven with 40 mg of trospium. Adverse events at the rivastigmine dose of9 mg when given with placebo trospium were limited to mild nausea.Adverse events at the rivastigmine dose of 24 mg when given with 40 mgof trospium also were mild nausea as well as abdominal pain, headacheand respiratory difficulty in addition to moderate anorexia. The peakplasma (maximum tolerated) concentration of rivastigmine measured invenous blood collected approximately 1 hour after the administration of24 mg of rivastigmine together with 40 mg of trospium was 39 ng/ml.Blood samples were not obtained after the 9 mg dose of rivastigminegiven with placebo trospium.

Subject (b) Age 26 years, weight 86 kg. The subject tolerated a dose of15 mg of rivastigmine when given with trospium placebo and of 18 mggiven when given with 40 mg of trospium. Adverse events reported at therivastigmine dose of 15 mg when given with placebo trospium weremoderate nausea and mild somnolence. Adverse events at the rivastigminedose of 18 mg when given with 40 mg of trospium were limited to mild drymouth. The peak plasma (maximum tolerated) concentration of rivastigminemeasured in venous blood collected approximately 1 hour after theadministration of 15 mg of rivastigmine given with placebo trospium was53 ng/ml and after the administration of 18 mg of rivastigmine givenwith 40 mg of trospium was 94 ng/ml.

Subject (c) Age 31 years, weight 64 kg. The subject tolerated a dose of15 mg of rivastigmine when given with trospium placebo and of 18 mg whengiven with 40 of trospium. Adverse events reported at the rivastigminedose of 15 mg when given with placebo trospium were limited to mild drymouth. Adverse events reported at the rivastigmine dose of 18 mg whengiven with 40 mg of trospium were mild dry mouth and moderate urinarydifficulty. The peak plasma (maximum tolerated) concentration ofrivastigmine measured in venous blood collected approximately 1 hourafter the administration of 15 mg of rivastigmine given with placebotrospium was 8.3 ng/ml and after the administration of 18 mg ofrivastigmine given with 40 mg of trospium was 131 ng/ml.

Accordingly, when given with 40 mg of trospium, Subject (a) tolerated 4times the maximum recommended single oral dose of rivastigmine (6 mg)and approximately 5.3 times the reported average maximum toleratedsingle oral dose of rivastigmine (about 4.5 mg) (Birks J, Grimley EvansJ, Iakovidou V, Tsolaki M, Holt F E. Rivastigmine for Alzheimer'sdisease. Cochrane Database Syst Rev. 2009 Apr. 15; (2): CD001191;Forette F, Anand R, Gharabawi G. “A phase II study in patients withAlzheimer's disease to assess the preliminary efficacy and maximumtolerated dose of rivastigmine (Exelon)”. Eur J Neurol. 1999 July;6(4):423-9). When given with 40 mg of trospium, Subjects (b) and (c)tolerated 3 times the maximum recommended single dose of rivastigmineand 4 times the average maximum tolerated single oral dose ofrivastigmine. Similarly, peak plasma concentrations of rivastigmine inthe 3 subjects given their maximum tolerated dose of this drug incombination with 40 mg of trospium averaged 88 ng/ml or 2.9 times the30.7 ng/ml average measured in 2 of these individuals when rivastigminewas given without trospium and some 7.3 times those reported in theliterature (about 12 ng/ml) (New Zealand Data Sheet, EXELON®Rivastigmine 5 and 10 cm² Transdermal Patch, Page 10, FIG. 2,www.medsafe.govt.nz/profs/datasheet/e/Exelonpatch.pdf) when the maximumrecommended single oral dose of rivastigmine (4.5 mg) was administered.The addition of trospium to rivastigmine therapy thus safely enablesboth an increase in the maximum tolerated dose and in the maximumtolerated plasma concentrations of the acetylcholinesterase inhibitor(AChEI).

Example 6

Tablets for IR oral administration containing 1.12 mg of granisetronhydrochloride formulated with a pharmaceutical carrier and tabletscontaining 10 mg of solifenacin succinate formulated with apharmaceutical carrier are distributed in two-compartment capsules asdescribed in GB 1,204,580, such that unit dosage forms containing 1.12mg of granisetron hydrochloride and 10 mg of solifenacin succinate areprepared.

Similarly, unit dosage forms containing 2.24 mg of granisetronhydrochloride and 10 mg of solifenacin succinate are prepared.

Example 7

Tablets for IR oral administration containing 2 mg of glycopyrroniumbromide formulated with a pharmaceutical carrier and tablets containing10 mg of domperidone formulated with a pharmaceutical carrier aredistributed in capsules as described in GB 1,204,580, such that unitdosage forms containing 2 mg of glycopyrronium bromide and 10 mg ofdomperidone are prepared.

Example 8 Maximum Tolerated Dose and Blood Level of Donepezil IncreaseEnabled by Co-Administered Solifenacin

In this single-blind study, healthy male volunteers were hospitalized ata Phase I Center (MT3D, Rue d'Alsace, 68250 Rouffach, France) for theonce daily oral administration of ascending doses of donepezilhydrochloride (“donepezil”) per protocol (5 mg to a possible maximum of40 mg in 5 mg increments as tolerated) together with placebo solifenacinsuccinate (“solifenacin”) and then with ascending amounts of donepezil(5 mg to a possible maximum of 40 mg in 5 mg increments as tolerated)together with active solifenacin. Placebo solifenacin or activesolifenacin (at a fixed dose of 10 mg per day) were given orally oncedaily 2 hours before donepezil administration. Venous blood wascollected for the measurement of plasma drug levels at their nominalpeaks (approximately 4 hour after donepezil administration). Subjectswere carefully monitored following drug administration until all adverseeffects had subsided. Safety and tolerability were evaluated based onsubject reports, physician observations and examinations, and theperformance of standard laboratory tests.

Subject (a) Age 25 years, weight 74 kg. The subject tolerated a dose of5 mg of donepezil when given with placebo solifenacin and 10 mg ofdonepezil when given with 10 mg of solifenacin. There were no adverseevents at 5 mg of donepezil given with placebo solifenacin. Adverseevents at 10 mg of donepezil given with 10 mg of solifenacin weremoderate abdominal pain and moderate headache. The peak plasma (maximumtolerated) concentration of donepezil after administration of 5 mg ofdonepezil with placebo solifenacin was 9.7 ng/ml and after 10 mg ofdonepezil given with 10 mg of solifenacin was 28.9 ng/ml.

Subject (b), Age 38 years, weight 71 kg. The subject tolerated a dose of5 mg of donepezil when given with placebo solifenacin and 15 mg ofdonepezil when given with 10 mg of solifenacin. There were no adverseevents at 5 mg of donepezil given with placebo solifenacin. Adverseevents at 15 mg of donepezil given with 10 mg of solifenacin weremoderate nausea and moderate dizziness. The peak plasma (maximumtolerated) concentration of donepezil after administration of 5 mg ofdonepezil with placebo solifenacin was 7.1 ng/ml and after 15 mg ofdonepezil with 10 mg of solifenacin was 36.5 ng/ml.

Subject (c), Age 27 years, weight 74 kgs. The subject tolerated a doseof 5 mg of donepezil when given with placebo solifenacin and 5 mg ofdonepezil when given with 10 mg of solifenacin. There were no adverseevents at 5 mg of donepezil given with placebo solifenacin or given withsolifenacin 10 mg. Adverse events with 10 mg of donepezil and placebosolifenacin consisted of severe anorexia, nausea, retching, vomiting,weakness, headache, moderate diarrhea, and mild sweating, dizziness,somnolence, hypersalivation, muscular cramps. Adverse events with 10 mgof donepezil when given with 10 mg of solifenacin consisted of severenausea and retching. The peak plasma (maximum tolerated) concentrationof donepezil after administration of 5 mg of donepezil with placebosolifenacin was 7.8 ng/ml and after 5 mg of donepezil given with 10 mgof solifenacin was 9.31 mg/ml.

Subject (d), Age 25 years, weight 79 kg. The subject tolerated a dose of15 mg of donepezil when given with placebo solifenacin and 15 mg ofdonepezil when given with 10 mg of solifenacin. Adverse events with 15mg of donepezil given with placebo solifenacin consisted of severeabdominal pain, weakness, moderate anorexia, sweating and dry mouth.Adverse events with 15 mg of donepezil given with 10 mg of solifenacinconsisted of severe headache. The peak plasma (maximum tolerated)concentration of donepezil after administration of 15 mg of donepezilwith placebo solifenacin was 41.7 ng/ml and after 15 mg of donepezilgiven with 10 mg of solifenacin was 48.9 mg/ml.

Subject (e), Age 29 years, weight 83 kg. The subject tolerated a dose of30 mg of donepezil when given with placebo solifenacin and 40 mg ofdonepezil when given with 10 mg of solifenacin. Adverse events at 30 mgof donepezil given with placebo solifenacin were moderate weakness, milddizziness and moderate hypersalivation. Adverse events at 40 mg ofdonepezil given with 10 mg of solifenacin were moderate abdominal painand severe headache. The clinical trial protocol specified that doseshigher than 40 mg of donepezil could not be administered. As aconsequence, donepezil dose escalation in this subject was discontinuedwhen he reached 40 mg of donepezil+solifenacin, although the subject hadnot reached maximum tolerated dose. The peak plasma (maximum tolerated)concentration of donepezil after administration of 30 mg of donepezilwith placebo solifenacin was 77.5 ng/ml and after 40 mg of donepezilwith 10 mg of solifenacin was 140 ng/ml.

Subject (f), Age 28 years, weight 57 kg. The subject tolerated a dose of5 mg of donepezil when given with placebo solifenacin and 10 mg ofdonepezil when given with 10 mg of solifenacin. There were no adverseevents at 5 mg of donepezil given with placebo solifenacin. Adverseevents at 10 mg of donepezil given with 10 mg of solifenacin werelimited to moderate dizziness. The peak plasma (maximum tolerated)concentration of donepezil after administration of 5 mg of donepezilwith placebo solifenacin was 8.85 ng/ml and after 10 mg of donepezilwith 10 mg of solifenacin was 30.5 ng/ml.

As these case reports indicate, in 4 out of 6 subjects, co-treatmentwith the peripheral anticholinergic, solifenacin, enabled the safe andtolerable administration of substantially higher daily doses of theAChEI, donepezil, than when the cholinesterase inhibitor was givenwithout active solifenacin. Indeed in this controlled study, six healthyvolunteers tolerated doses of donepezil combined with solifenacin, thatranged from 5 to (at least) 40 mg and averaged 16 mg or nearly 1.7-foldthe maximum recommended dose of this donepezil formulation and nearly2.2-times its average maximum tolerated dose (about 7.3 mg) incontrolled clinical trials (Lockhart I A, Mitchell S A, Kelly S. Safetyand tolerability of donepezil, rivastigmine and galantamine for patientswith Alzheimer's disease: systematic review of the ‘real-world’evidence. Dement Geriatr Cogn Disord. 2009; 28(5):389-403). Adverseevents at the first intolerable dose of donepezil given withoutsolifenacin substantially exceeded those at the same donepezil dose whengiven with the anticholinergic.

In addition, co-administration of the anticholinergic solifenacin, atits maximum recommended dose, permitted the AChEI to safely andtolerably attain peak plasma concentrations averaging 49 ng/ml, incomparison to only 26 ng/ml when maximum tolerated doses of donepezilwere given with placebo solifenacin. Peak donepezil levels thusincreased some 2.6 fold with combined therapy. The drug dose-plasmalevel relation (dose proportionality) for both AChEIs are reportedlylinear in the relevant dose ranges. Thus the combined use of aperipheral anticholinergic and an AChEI is again shown to safely enablea substantial increase in peak circulating AChEI concentrations in humansubjects. Based on previously cited results from multiple animal andhuman studies, the ability to safely increase the dose and thus exposureto AChEI can be expected to augment their cognitive benefit in patientswith Alzheimer's type dementia.

Table 1 below summarizes the MTD and the plasma donepezil concentrationof the six above subjects.

TABLE 1 Maximum Tolerated Dose (MTD) and Plasma Concentrations ofDonepezil (Donep) Given Alone (MTD-1) or with Solifenacin (Solif) 10mg/day (MTD-2) MTD-1 MTD-2 Ratio Donep Plasma Subject Donep Donep + MTD-Concentr. (ng/ml) Ratio of No. alone Solif 2/MTD-1 MTD-1 MTD-2 Concentr.(a) 5 10 2.0 9.7 28.9 2.98 (b) 5 15 3.0 7.11 36.5 5.13 (c) 5 5 1.0 7.89.31 1.19 (d) 15 15 1.0 41.7 48.9 1.17 (e) 30 ≧40 ≧1.4 77.5 >140 >1.81(f) 5 10 2.0 8.85 30.5 3.45In two subjects, (c) and (d), the MTD of donepezil with or withoutsolifenacin did not change and the donepezil plasma concentrationsincreased by 20% only after its administration in combination withsolifenacin. In the other subjects, after administration ofdonepezil/solifenacin combination a 33-300% increase of the donepezilMTD induced an 80%-500% increase of the plasma concentration, thusconfirming that the AChEI plasma concentrations remarkably increase ifthe dose of said AChEI increases.

Example 9

(a) Tablets containing 10 mg of solifenacin succinate formulated with apharmaceutical carrier and tablets containing 10 mg of domperidoneformulated with a pharmaceutical carrier distributed in capsules asdescribed in GB 1,204,580, such that unit dosage forms containing 10 mgof solifenacin succinate and 10 mg of domperidone are prepared.

(b) In the same manner, unit dosage forms consisting of capsules eachcontaining one tablet wherein 5 mg of ondansetron hydrochloridedihydrate are formulated with a pharmaceutical carrier and one tabletwherein 10 mg of solifenacin succinate are formulated with apharmaceutical carrier, are prepared.

(c) Similarly, unit dosage forms consisting of capsules each containingone film-coated tablet wherein 1.12 mg of granisetron hydrochloride areformulated with a pharmaceutical carrier and one tablet wherein 10 mg ofsolifenacin succinate are formulated with a pharmaceutical carrier, areprepared.

(d) Analogously, unit dosage forms consisting of capsules eachcontaining one tablet wherein 10 mg of metoclopramide, asmonohydrochloride monohydrate, are formulated with a pharmaceuticalcarrier and one tablet wherein 10 mg of solifenacin succinate areformulated with a pharmaceutical carrier, are prepared.

(e) Likewise, unit dosage forms consisting of capsules each containingone film-coated tablet wherein 1.12 mg of granisetron hydrochloride areformulated with a pharmaceutical carrier and one tablet wherein 10 mg ofsolifenacin succinate are formulated with a pharmaceutical carrier, areprepared.

Example 10

Capsules for oral administration are prepared by mixing the followingingredients:

Ingredients Parts by weight Solifenacin succinate 2,000 Metoclopramidemonohydrochloride monohydrate 1,178 Lactose USP 7,500 Colloidal silicondioxide (Aerosil ®) 50

After mixing, the mixture is screened through a 40 mesh screen andintroduced in two-piece hard gelatin capsule No. 3 containing 10 mg ofmetoclopramide (as monohydrochloride monohydrate) and 20 mg ofsolifenacin succinate.

Similarly, capsules containing 15 mg of solifenacin succinate and 10 mgof metoclopramide (as monohydrochloride monohydrate) are prepared.

Example 11

Tablets for IR oral administration containing 2 mg of glycopyrroniumbromide formulated with a pharmaceutical carrier and tablets containing2 mg of granisetron hydrochloride formulated with a pharmaceuticalcarrier are distributed in capsules as described in GB 1,204,580, suchthat unit dosage forms containing 2 mg of glycopyrronium bromide and 2mg of granisetron hydrochloride.

Example 12

Capsules for oral administration are prepared by mixing the followingingredients:

Ingredients Parts by weight Trospium chloride 2,000 Ondansetronhydrochloride dihydrate 1,000 Lactose USP 7,500 Colloidal silicondioxide (Aerosil ®) 50

After mixing, the mixture is screened through a 40 mesh screen andintroduced in two-piece hard gelatin capsule No. 3 containing 8 mg ofondansetron (as hydrochloride dihydrate) and 20 mg of trospium chloride.

Similarly, capsules containing 25 mg of trospium chloride and 8 mg ofondansetron (as hydrochloride dihydrate) are prepared.

Example 13

Capsules for oral administration are prepared by mixing the followingingredients:

Ingredients Parts by weight Trospium chloride 4,000 Granisetronhydrochloride 112 Lactose USP 7,500 Colloidal silicon dioxide(Aerosil ®) 88

After mixing, the mixture is screened through a 40 mesh screen andintroduced in two-piece hard gelatin capsule No. 2 containing 40 mg oftrospium chloride and 1 mg of granisetron (as hydrochloride).

All references, including publications, patent applications, and patentscited herein are hereby incorporated by reference to the same extent asif each reference were individually and specifically indicated to beincorporated by reference and were set forth in its entirety herein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) is to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Although preferred embodiments have been depicted and described indetail herein, it will be apparent to those skilled in the relevant artthat various modifications, additions, substitutions, and the like canbe made without departing from the spirit of the invention and these aretherefore considered to be within the scope of the invention as definedin the claims which follow.

The invention claimed is:
 1. A pharmaceutical composition comprising (a)a non-selective, peripheral anticholinergic agent (nsPAChA) selectedfrom the group consisting of propiverine and pharmaceutically acceptablesalts thereof, in an amount which is equivalent to from 15 mg to 240 mgof propiverine hydrochloride; trospium pharmaceutically acceptablesalts, in an amount which is equivalent to from 20 mg to 480 mg oftrospium chloride; and glycopyrronium-pharmaceutically acceptable salts,in an amount which is equivalent to from 2 mg to 16 mg of glycopyrroniumbromide; and (b) a non-anticholinergic antiemetic agent (naAEA); andwherein the composition does not include a cannabinoid.
 2. Thepharmaceutical composition according to claim 1, further comprising anacetylcholine esterase inhibitor (AChEI).
 3. The pharmaceuticalcomposition according to claim 1, further comprising a pharmaceuticalcarrier.